Dosing regimens for echinocandin class compounds

ABSTRACT

The invention features pharmaceutical compositions, methods, and kits featuring dosing gimens and oral dosage formulations for administration of echinocandin class compounds.

This application claims benefit of the U.S. Provisional Application No.61/612,676, filed Mar. 19, 2012, and U.S. Provisional Application No.61/707,142, filed Sep. 28, 2012, each of which is incorporated herein byreference.

BACKGROUND OF THE INVENTION

This invention relates to the field of treatment of fungal infections.

The need for novel antifungal treatments is significant, and isespecially critical in the medical field. Immunocompromised patientsprovide perhaps the greatest challenge to modern health care delivery.During the last three decades there has been a dramatic increase in thefrequency of fungal infections in these patients (Herbrecht, Eur. J.Haematol., 56:12, 1996; Cox et al., Curr. Opin. Infect. Dis., 6:422,1993; Fox, ASM News, 59:515, 1993). Deep-seated mycoses are increasinglyobserved in patients undergoing organ transplants and in patientsreceiving aggressive cancer chemotherapy (Alexander et al., Drugs,54:657, 1997). The most common pathogens associated with invasive fungalinfections are the opportunistic yeast, Candida albicans, and thefilamentous fungus, Aspergillus fumigatus (Bow, Br. J. Haematol., 101:1,1998; Wamock, J. Antimicrob. Chemother., 41:95, 1998). There are anestimated 200,000 patients per year who acquire nosocomial fungalinfections (Beck-Sague et al., J. Infect. Dis., 167:1247, 1993). Alsoadding to the increase in the numbers of fungal infections is theemergence of Acquired Immunodeficiency Syndrome (AIDS) where virtuallyall patients become affected with some form of mycoses during the courseof the disease (Alexander et al., Drugs, 54:657, 1997; Hood et al., J.Antimicrob. Chemother., 37:71, 1996). The most common organismsencountered in these patients are Cryptococcus neoformans, Pneumocystiscarinii, and C. albicans (HIV/AIDS Surveillance Report, 1996, 7(2),Year-End Edition; Polis, M. A. et al., AIDS: Biology, Diagnosis,Treatment and Prevention, fourth edition, 1997). New opportunisticfungal pathogens such as Penicillium marneffei, C. krusei, C. glabrata,Histoplasma capsulatum, and Coccidioides immitis are being reported withregularity in immunocompromised patients throughout the world.

The development of antifungal treatment regimens has been a continuingchallenge. Currently available drugs for the treatment of fungalinfections include amphotericin B, a macrolide polyene that interactswith fungal membrane sterols, flucytosine, a fluoropyrimidine thatinterferes with fungal protein and DNA biosynthesis, and a variety ofazoles (e.g., ketoconazole, itraconazole, and fluconazole) that inhibitfungal membrane-sterol biosynthesis (Alexander et al., Drugs, 54:657,1997). Even though amphotericin B has a broad range of activity and isviewed as the “gold standard” of antifungal therapy, its use is limiteddue to infusion-related reactions and nephrotoxicity (Wamock, J.Antimicrob. Chemother., 41:95, 1998). Flucytosine usage is also limiteddue to the development of resistant microbes and its narrow spectrum ofactivity. The widespread use of azoles is causing the emergence ofclinically-resistant strains of Candida spp. Due to the problemsassociated with the current treatments, there is an ongoing search fornew treatments.

When the echinocandin caspofungin was approved for sale in 2001, itrepresented the first new class of antifungal agents to be approved inover a decade. Since that time, two other echinocandin antifungals,anidulafungin and micafungin, have been approved in various markets.Each agent in this class of compound acts by inhibition of β-1, 3-glucansynthase, which is a key enzyme in the synthesis of glucan in the cellwall of many fungi. All three of these drugs are made semisynthetically,starting with natural products obtained through fermentation.

The echinocandins are a broad group of antifungal agents that typicallyare comprised of a cyclic hexapeptide and lipophilic tail, the latter ofwhich is attached to the hexapeptide core through an amide linkage.Although many echinocandins are natural products, the clinicallyrelevant members of this class have all been semisynthetic derivatives.Although the naturally occurring echinocandins possess some degree ofanti-fungal activity, they have not been suitable as therapeutics,primarily because of poor aqueous solubility, insufficient potency,and/or hemolytic action. The approved echinocandins are the products ofintense efforts to generate derivatives or analogs that maintain orimprove upon the glucan synthase inhibition, but do not cause thehemolytic effects. As therapeutic agents, they are attractive compoundsin terms of their systemic half-lives, large therapeutic windows, safetyprofiles, and relative lack of interactions with other drugs.Unfortunately, the poor intestinal absorption of these compounds hasrelegated them to delivery by intravenous infusion. Although patientsreceiving these drugs are often hospitalized with serious infections,the ability to transition patients from intravenous delivery in ahospital setting to oral delivery in a home setting would be verydesirable, especially considering the course of the regimen commonlyexceeds 14 days. In addition, an oral echinocandin may expand the use ofthis drug class to include patients that present with mild fungalinfections.

SUMMARY OF THE INVENTION

We have discovered dosing regimens and oral dosage formulations foradministration of echinocandin class compounds.

In a first aspect, the invention features a method of treating a fungalinfection in a subject by (i) administering a loading-dose of anechinocandin class compound to the subject; and (ii) administering oneor more maintenance doses of the echinocandin class compound to thesubject, wherein each of the loading-dose and the maintenance doses areadministered in an amount that together are sufficient to treat thefungal infection. For example, the loading dose can be administered byinjection (e.g., subcutaneously) or orally followed by maintenancedosing administered orally, intravenously, nasally, subcutaneously ortransdermally. In one embodiment, the loading-dose is intravenouslyadministered. For example, the intravenously (e.g., as a bolus orinfusion) administered loading-dose can be administered in an amountsufficient to produce a mean steady-state concentration of theechinocandin class compound in plasma of from 100 ng/mL to 20,000 ng/mL(e.g., from 100 to 500, 400 to 1,000, 800 to 3,000, 2,000 to 7,000,6,000 to 10,000, 8,000 to 14,000, or 12,000 to 20,000 ng/mL); can beintravenously administered to the subject in an amount of echinocandinclass compound per body weight of subject of from 0.5 mg/kg to 20 mg/kg(e.g., from 0.5 to 2.0, 1.0 to 4.0, 3.0 to 10, 8.0 to 15, or 13 to 20mg/kg); and/or can be intravenously administered to the subject in anamount of echinocandin class compound of from 25 mg to 1,400 mg (e.g.,from 25 to 50, 40 to 80, 75 to 130, 125 to 170, 150 to 200, 190 to 250,230 to 500, 450 to 750, 650 to 1,000, or 900 to 1,400 mg) over a 24 hourperiod. Alternatively, the loading-dose can be orally administered. Forexample, the orally administered to the subject in an amount ofechinocandin class compound of from 250 mg to 4,000 mg (e.g., from 250to 500, 400 to 800, 750 to 1300, 1250 to 1700, or 1,500 to 4,000 mg)over a 24 hour period. In an embodiment of any of the above methods, themaintenance doses can be administered over a period of from 2 to 45 days(e.g., 2 to 10, 7 to 14, 10 to 21, or 18 to 30 days, or 24 to 45 days)following the initiation of the treatment. The maintenance doses can beadministered, for example, at a rate of from once per week to threetimes daily (e.g., once per every 5-7 days, once per every 3 days, everyother day, once daily, twice daily, or three times daily). Theechinocandin class compound can be a compound of any of formulas (I),(II), (III), (IV), (V), (VI), (VII), (VIIII), or (IX), or selected fromanidulafungin, caspofungin, micafungin, compound 22, or any otherechinocandin class compound described herein, or a pharmaceuticallyacceptable salt thereof. In certain embodiments, the loading doseincludes intravenous administration of from 50 to 400 mg (e.g., 50 to125, 75 to 300, or 100 to 400 mg) of compound 22, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the method includesmaintenance dosing that includes oral administration of from 250 to 800mg (e.g., 250 to 300, 275 to 450, 425 to 625, or 600 to 800 mg) ofcompound 22, or a pharmaceutically acceptable salt thereof, every day orevery other day or every three days. In some embodiments, the methodincludes maintenance dosing that includes subcutaneous administration offrom 25 to 150 mg (e.g., 25 to 30, 35 to 45, 30 to 70, 50 to 100, 70 to120 or 110 to 150 mg) of compound 22, or a pharmaceutically acceptablesalt thereof, every day or every other day or once every three days oronce every five days. In some embodiments, the method includesmaintenance dosing that includes IV bolus administration of from 25 to150 mg (e.g., 25 to 30, 35 to 45, 30 to 70, 50 to 100, 70 to 120 or 110to 150 mg) of compound 22, or a pharmaceutically acceptable saltthereof, every day or every other day or every three days or once everyfive days.

In one particular embodiment of any of the above methods, step (ii)includes orally administering to the subject a pharmaceuticalcomposition in unit dosage form including: (a) a drug selected fromechinocandin class compounds, and salts thereof; and (b) from 0.5% to90% (w/w) (e.g., from 0.5% to 5%, 2.5% to 7.5%, 7% to 12%, 10% to 25%,25% to 35%, 30% to 50%, or 40% to 90% (w/w)) of an additive, wherein theadditive is present in an amount sufficient to increase the oralbioavailability of the echinocandin class compounds, or salt thereof. Inparticular embodiments, the additive is selected from acyl carnitines,alkyl saccharides, ester saccharides, amido fatty acids, ammoniumsulfonate surfactants, bile acids and salts (including cholic acid andsalts thereof), chitosan and derivatives thereof, fatty acids and saltsor esters thereof, glycerides, hydrophilic aromatic alcohols, pegylatedphospholipids, peptide epithelial tight junction modulators,phospholipids, polyethylene glycol alkyl ethers, polyglycolizedglycerides, polyglycerol fatty acid esters, polysorbate surfactants,carboxylic acids, polyethylene glycols, and mixtures thereof.

In particular embodiments of the above method, the loading-dose isadministered intravenously (e.g., by intravenous bolus or infusion) andthe maintenance dose is administered orally; the loading-dose isadministered subcutaneously and the maintenance dose is administeredorally; the loading-dose is administered intravenously (e.g., byintravenous bolus or infusion) and the maintenance dose is administeredsubcutaneously; the loading-dose is administered subcutaneously and themaintenance dose is administered subcutaneously; the loading-dose isadministered orally and the maintenance dose is administered orally; orthe loading-dose is administered intravenously (e.g., by intravenousbolus or infusion) and the maintenance dose is administered by injection(e.g., by intravenous bolus or infusion, or by subcutaneous injection).In particular embodiments of the method including an intravenous bolus,the amount of echinocandin class compound administered is from 50 mg to500 mg (e.g., from 50 to 100, 100 to 200, 150 to 225, 200 to 300, 275 to400, or 400 to 500 mg) in a single bolus injection.

In a related aspect, the invention features a pharmaceutical compositionin unit dosage form including: (a) an echinocandin class compound, or apharmaceutically acceptable salt thereof; and (b) from 0.5% to 90% (w/w)(e.g., from 0.5% to 5%, 2.5% to 7.5%, 7% to 12%, 10% to 25%, 25% to 35%,30% to 50%, or 40% to 90% (w/w)) of an additive, wherein the additive ispresent in an amount sufficient to increase the oral bioavailability ofthe echinocandin class compound, or salt thereof. In particularembodiments, the additive is selected from acyl carnitines, alkylsaccharides, ester saccharides, amido fatty acids, ammonium sulfonatesurfactants, bile acids and salts (including cholic acid and saltsthereof), chitosan and derivatives thereof, fatty acids and salts oresters thereof, glycerides, hydrophilic aromatic alcohols, pegylatedphospholipids, peptide epithelial tight junction modulators,phospholipids, polyethylene glycol alkyl ethers, polyglycolizedglycerides, polyglycerol fatty acid esters, polysorbate surfactants,carboxylic acids, polyethylene glycols, and mixtures thereof. In certainembodiments, the pharmaceutical composition can include from 2% to 90%(w/w) (e.g., 3% to 6%, 3% to 8%, 5% to 12%, 8% to 16%, 15% to 25%, 25%to 35%, 35% to 65%, or 65% to 90% (w/w)) alkyl saccharide or estersaccharide, optionally further including from 0.5% to 15% (w/w) (e.g.,0.5% to 2.5%, 1% to 4%, 3% to 7%, 5% to 10%, 7% to 12%, or 11% to 15%(w/w)) polysorbate surfactant. In particular embodiments, thepharmaceutical composition can include from 2% to 90% (w/w) (e.g., 3% to6%, 3% to 8%, 5% to 12%, 8% to 16%, 15% to 25%, 25% to 35%, 35% to 65%,or 65% to 90% (w/w)) glyceride, optionally further including from 0.5%to 15% (w/w) (e.g., 0.5% to 2.5%, 1% to 4%, 3% to 7%, 5% to 10%, 7% to12%, or 11% to 15% (w/w)) polysorbate surfactant. In some embodiments,the pharmaceutical composition can include from 1% to 90% (w/w) (e.g.,2% to 5%, 3% to 8%, 5% to 12%, 10% to 18%, 15% to 24%, 20% to 30%, 25%to 35%, 30% to 50%, 50% to 70%, or 65% to 90% (w/w)) fatty acid, or asalt or ester thereof. In certain embodiments, the pharmaceuticalcomposition can include from 1% to 90% (w/w) (e.g., 2% to 6%, 5% to 12%,10% to 18%, 15% to 25%, 20% to 35%, 30% to 45%, 40% to 60%, or 55% to90% (w/w)) acyl carnitine, optionally further including a buffer toform, upon exposure to water, a solution having a pH of from 2.5 to 8.In some embodiments, the pharmaceutical composition can include from 1%to 90% (w/w) (e.g., 2% to 5%, 3% to 8%, 5% to 12%, 10% to 18%, 15% to24%, 20% to 30%, 25% to 35%, 30% to 50%, 50% to 70%, or 65% to 90%(w/w)) carboxylic acid, or a salt thereof. In certain embodiments, thepharmaceutical composition can include from 1% to 90% (w/w) (e.g., 2% to5%, 3% to 8%, 5% to 12%, 10% to 18%, 15% to 24%, 20% to 30%, 25% to 35%,30% to 50%, 50% to 70%, or 65% to 90% (w/w)) polyethylene glycols. Inparticular embodiments, the pharmaceutical composition includes an alkylsaccharide or ester saccharide, wherein the ratio by weight of theechinocandin class compound to the alkyl saccharide, or to the estersaccharide, is from 1:1 to 1:20 (e.g., from 1:1 to 1:3, 1:2 to 1:5, 1:4to 1:10, or 1:5 to 1:20). In certain embodiments, the pharmaceuticalcomposition includes a glyceride, wherein the ratio by weight of theechinocandin class compound to the glyceride is from 1:1 to 1:20 (e.g.,from 1:1 to 1:3, 1:2 to 1:5, 1:4 to 1:10, or 1:5 to 1:20). In someembodiments, the pharmaceutical composition includes a fatty acid, or asalt or ester thereof, wherein the ratio by weight of the echinocandinclass compound to the fatty acid, or a salt thereof, is from 1:1 to 1:30(e.g., from 1:1 to 1:3, 1:2 to 1:5, 1:4 to 1:10, or 1:10 to 1:30). Inparticular embodiments, the pharmaceutical composition includes an acylcarnitine (e.g., palmitoyl carnitine or lauroyl carnitine), wherein theratio by weight of the echinocandin class compound to the acyl carnitineis from 1:1 to 1:30 (e.g., from 1:1 to 1:3, 1:2 to 1:5, 1:4 to 1:10, or1:10 to 1:30). In particular embodiments, the pharmaceutical compositionincludes a carboxylic acid (e.g., citric acid, succinic acid, tartaricacid, fumaric acid, maleic acid, malonic acid, glutaric acid, adipicacid, lactic acid, malic acid, L-glutamic acid, L-aspartic acid,gluconic acid, glucuronic acid, salicylic acid, or mixtures thereof),wherein the ratio by weight of the echinocandin class compound to thecarboxylic acid is from 1:1 to 1:30 (e.g., from 1:1 to 1:3, 1:2 to 1:5,1:4 to 1:10, or 1:10 to 1:30). In particular embodiments, thepharmaceutical composition includes a polyethylene glycol (e.g., PEG100, PEG 400, PEG 1,000, etc.), wherein the ratio by weight of theechinocandin class compound to the polyethylene glycol is from 1:1 to1:30 (e.g., from 1:1 to 1:3, 1:2 to 1:5, 1:4 to 1:10, or 1:10 to 1:30).

In an embodiment of any of the above pharmaceutical compositions, theunit dosage form includes from 50 to 4,000 mg (e.g., from 50 to 300,from 250 to 750, from 500 to 1,500, or from 1,000 to 4,000 mg) of theechinocandin class compound. The unit dosage form can be formulated forimmediate release.

The pharmaceutical composition can contain an echinocandin classcompound of any of formulas (I), (II), (III), (IV), (V), (VI), (VII),(VIIII), or (IX), or selected from anidulafungin, caspofungin,micafungin, compound 22, or any other echinocandin class compounddescribed herein, or a pharmaceutically acceptable salt thereof.

In an embodiment of any of the above pharmaceutical compositions, theadditive is present in an amount sufficient to produce, upon oraladministration to a subject, a mean bioavailability of 3% to 30% (e.g.,4±2%, 6±2%, 8±2%, 10±2%, 12±3%, 15±3%, 18±4%, 22±6%, or 27±3%)

In a related aspect, the invention features a method of treating afungal infection in a subject by orally administering to the subject apharmaceutical composition of the invention, wherein the pharmaceuticalcomposition is administered in an amount effective to treat theinfection.

The invention further features a method of treating a fungal infectionin a subject by subcutaneously administering to the subject an aqueoussolution including compound 22, or a pharmaceutically acceptable saltthereof, in an amount that is sufficient to treat the fungal infection.In particular embodiments, the aqueous solution can be subcutaneouslyadministered to the subject twice daily, daily, every other day, everythree days, or once weekly over a period of at least 2 weeks, 3 weeks, 4weeks, 2 months, 3 months, or 4 months. The aqueous solution can includefrom 25 mg/mL to 500 mg/mL of compound 22, or a pharmaceuticallyacceptable salt thereof (e.g., 30±5, 40±10, 50±10, 60±10, 70±10, 80±10,100±15 mg/mL, 130±20 mg/mL, 160±30 mg/mL, 190±30 mg/mL, 250±50 mg/mL or400±100 mg/mL). In particular embodiments, from 0.05 mL to 2.0 mL of theaqueous solution are administered to the subject daily. In someembodiments, the amount of compound 22, or a pharmaceutically acceptablesalt thereof, subcutaneously administered to the subject is from 10 mgto 100 mg (e.g., 15±5, 25±10, 50±20, 70±25, or 80±20 mg) daily.

In a related aspect, the invention features a device for injecting anaqueous solution of compound 22, or a pharmaceutically acceptable saltthereof, into a subject, including a container holding from 0.05 mL to10 mL of the aqueous solution (e.g., from 0.2 mL to 0.5 mL, 0.5 mL to 3mL, 2 mL to 5 mL, 4 mL to 7 mL, or 6 mL to 10 mL of the aqueoussolution) and a needle. For example, the device can be a pen injectordevice holding a prefilled cartridge, such as a metered pen device witha micro needle. In particular embodiments, the container is a cartridge.In particular embodiments, the device is a prefilled syringe containing0.05 mL to 1 mL (e.g., from 0.2 mL to 0.5 mL, or 0.5 mL to 1 mL) of theaqueous solution. In still other embodiments, the aqueous solutionincludes from 25 mg/mL to 500 mg/mL of compound 22, or apharmaceutically acceptable salt thereof e.g., (30±5, 40±10, 50±10,60±10, 70±10, 80±10, 100±15 mg/mL, 130±20 mg/mL, 160±30 mg/mL, 190±30mg/mL, 250±50 mg/mL or 400±100 mg/mL).

The invention further features a method of treating a fungal infectionin a subject by administering to the subject an intravenous bolus of anaqueous solution including compound 22, or a pharmaceutically acceptablesalt thereof, in an amount that is sufficient to treat the fungalinfection. In particular embodiment, the aqueous solution includes from25 mg/mL to 500 mg/mL (e.g., 30±5, 40±10, 50±10, 60±10, 70±10, 80±10,100±15 mg/mL, 130±20 mg/mL, 160±30 mg/mL, 190±30 mg/mL, 250±50 mg/mL or400±100 mg/mL) of compound 22, or a pharmaceutically acceptable saltthereof. The bolus injection can be administered to the subject daily,every other day, or every three days, or every 4-7 days, or every weekover a period of at least 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months,or 4 months. In some embodiments, the amount of compound 22, or apharmaceutically acceptable salt thereof, administered as an intravenousbolus to the subject is from 25 mg to 500 mg (e.g., 30±5, 40±10, 50±10,75±25, 100±25, 150±25, 200±50, 300±100, or 500±100 mg) per bolusadministration.

The invention further features an echinocandin class compound, or a saltthereof, in unit dosage form comprising from 40 to 90% (w/w) non aqueoussolvent or aprotic solvent (e.g., ethanol, ethylene glycol, polyethyleneglycol (e.g., PEG200, PEG400, PEG800), or propylene glycol) and one ormore absorption enhancing excipients described herein. Optionally, theechinocandin class compound is compound 22, or a salt thereof.

The invention further features a method of treating a fungal infectionin a subject in need thereof by administering to the subject anintravenous infusion of an aqueous solution including compound 22, or apharmaceutically acceptable salt thereof, in an amount that issufficient to treat the fungal infection. In certain embodiments, theinfusion solution includes from 0.5 mg/mL to 3.0 mg/mL (e.g., 0.75±0.25,1.0±0.25, 1.5±0.25, 2.0±0.25, or 2.50±0.50 mg/mL) of compound 22, or apharmaceutically acceptable salt thereof. In particular embodiments ofthe method, compound 22, or a pharmaceutically acceptable salt thereof,is administered to the subject in two or more intravenous infusions orintravenous boluses administered once every 5 to 8 days (e.g., weeklyfor a period of at least 4 weeks, 6 weeks, 8 weeks, or 12 weeks). Inanother embodiment, the method further includes, following theintravenous infusion, orally administering 200 mg to 1,000 mg (e.g.,250±50, 300±50, 400±50, 500±50, 600±50, 700±50, 800±50, or 900±50 mg) ofcompound 22, or a pharmaceutically acceptable salt thereof, to thesubject daily for a period of at least 5 to 8 days (e.g., daily for aperiod of at least 2 weeks, 4 weeks, 6 weeks, 8 weeks, or 12 weeks).

The invention features a pharmaceutical composition in unit dosage formincluding from 25 mL to 500 mL (e.g., 50±25, 100±25, 150±50, 250±50,350±50, or 400±100 mL) of an aqueous solution including from 0.50 mg/mLto 3 mg/mL (e.g., 0.75±0.25, 1.0±0.25, 1.5±0.25, 2.0±0.25, or 2.50±0.50mg/mL) compound 22, or a pharmaceutically acceptable salt thereof,wherein the unit dosage form is suitable for intravenous infusion into asubject.

In a related aspect, the invention features a pharmaceutical compositionin unit dosage form including from 1 mL to 10 mL (e.g., 1.5±0.5, 3±1,5±2, or 7.5±2.5 mL) of an aqueous solution including from 25 mg/mL to500 mg/mL (e.g., 30±5, 40±10, 50±10, 60±10, 70±10, 80±10, 100±15 mg/mL,130±20 mg/mL, 160±30 mg/mL, 190±30 mg/mL, 250±50 mg/mL or 400±100 mg/mL)compound 22, or a pharmaceutically acceptable salt thereof, wherein theunit dosage form is suitable for intravenous bolus injection into asubject.

In still another related aspect, the invention features a pharmaceuticalcomposition in unit dosage form including from 0.05 mL to 1.0 mL (e.g.,0.2±0.1, 0.5±0.25, 0.75±0.25, or 0.9±0.1 mL) of an aqueous solutionincluding from 85 mg/mL to 300 mg/mL (e.g., 100±15 mg/mL, 130±20 mg/mL,160±30 mg/mL, 190±30 mg/mL, 250±50 mg/mL or 400±100 mg/mL) compound 22,or a pharmaceutically acceptable salt thereof, wherein the unit dosageform is suitable for subcutaneous injection into a subject.

In any of the above unit dose pharmaceutical compositions formulated forinjection, the pharmaceutical composition can (i) be free of stabilizingsugars (e.g., fructose, sucrose, trehalose or combinations thereof),(ii) include a surfactant (e.g., Tween 20, Tween 80, or any surfactantdescribed herein), (iii) a bulking agent (e.g., mannitol, or anothersugar alcohol), and/or (iv) a buffer (i.e., any buffer describedherein). The aqueous solution in the unit dosage form can be prepared byreconstituting a lyophilized powder including compound 22, or apharmaceutically acceptable salt thereof. Alternatively, the aqueoussolution in the unit dosage form can be prepared by reconstituting aliquid concentrate including compound 22, or a pharmaceuticallyacceptable salt thereof.

The invention features a kit including (i) a unit dosage form containinga lyophilized powder including compound 22, or pharmaceuticallyacceptable salt thereof, and (ii) instructions for reconstituting thelyophilized powder with an aqueous solution to form a pharmaceuticalcomposition suitable for injection into a subject.

In a related aspect, the invention features a kit including (i) a unitdosage form containing a liquid concentrate including compound 22, orpharmaceutically acceptable salt thereof, and (ii) instructions forreconstituting the liquid concentrate with an aqueous solution to form apharmaceutical composition suitable for injection into a subject.

In any of the above kits, the unit dosage form can (i) be free ofstabilizing sugars (e.g., fructose, sucrose, trehalose or combinationsthereof), (ii) include a surfactant (e.g., Tween 20, Tween 80, or anysurfactant described herein), (iii) a bulking agent (e.g., mannitol, oranother sugar alcohol), and/or (iv) a buffer (i.e., any buffer describedherein).

The invention further features an acid addition salt of an echinocandinclass compound in unit dosage form, wherein the acid addition salt isderived from an organic acid (e.g., acetic, lactic, palmoic, maleic,citric, cholic acid, capric acid, caprylic acid, lauric acid, glutaric,glucuronic, glyceric, glycocolic, glyoxylic, isocitric, isovaleric,lactic, malic, oxalo acetic, oxalosuccinic, propionic, pyruvic,ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric,methanesulfonic, toluenesulfonic, or trifluoroacetic acid salts).Optionally, the acid addition salt includes an absorption enhancingagent. Optionally, the echinocandin class compound is an acid additionsalt of compound 22. The unit dosage form can further include one ormore absorption enhancing excipients described herein.

The invention further features an echinocandin class compound, or a saltthereof, in unit dosage form including from 2 to 80% (w/w) citric acid.The unit dosage form can further include one or more additionalabsorption enhancing excipients described herein.

The invention also features kits, including: a) any pharmaceuticalcomposition of the invention; and b) instructions for administering thepharmaceutical composition to a subject diagnosed with a fungalinfection.

By “acyl carnitine” is meant a chemical moiety with the formula:

and salts thereof, wherein R is a partially-saturated straight chain orbranched hydrocarbon group having between 8 and 26 carbon atoms. Acylcarnitines are derived carnitine (D or L form, or a mixture thereof) anda fatty acid. The acyl carnitine can be an ester of a fatty acid having16 carbon atoms and 0, 1 or 2 double bonds (C16:0; C16:1 and C16:2),those with 18 carbon atoms and 1, 2 or 3 double bonds (C18:1; C18:2; andC18:3), those with 20 carbon atoms and 1, 2 or 4 double bonds (C20:1;C20:2; and C20:4), or those with 22 carbon atoms and 4, 5 or 6 doublebonds (C22:4; C22:5 and C22:6). Acyl carnitines include, withoutlimitation, 4, 7, 10, 13, 16, 19 docosahexanoyl carnitine, oleoylcarnitine, palmitoyl carnitine, decanoyl carnitine, dodecanoylcarnitine, myristoyl carnitine, and stearoyl carnitine.

As used herein, the term “administration” or “administering” refers toadministration by any route, such as by injection (e.g., intravenousadministration by bolus injection or infusion, subcutaneousadministration), transdermal administration, topical administration,intranasal, or peroral administration of a drug to a subject.

By “additive” is meant those components of a pharmaceutical compositioncontaining a drug (e.g., an echinocandin class compound) in oral dosageform which increase the oral bioavailability of the drug when orallyadministered simultaneously with the drug. Additives of the inventionacyl carnitines, alkyl saccharides, ester saccharides, amido fattyacids, ammonium sulfonate surfactants, bile acids and salts (includingcholic acid and salts thereof), chitosan and derivatives thereof, fattyacids and salts or esters thereof, glycerides, hydrophilic aromaticalcohols, pegylated phospholipids, peptide epithelial tight junctionmodulators, phospholipids, polyethylene glycol alkyl ethers,polyglycolized glycerides, polyglycerol fatty acid esters, polysorbatesurfactants, carboxylic acids, polyethylene glycols, and mixturesthereof.

By “an amount sufficient” is meant the amount of an additive required toincrease the oral bioavailability of a drug.

By “fungal infection” is meant the invasion of a host by pathogenicfungi. For example, the infection may include the excessive growth offungi that are normally present in or on the body of a human or growthof fungi that are not normally present in or on a human. More generally,a fungal infection can be any situation in which the presence of afungal population(s) is damaging to a host body. Thus, a human is“suffering” from a fungal infection when an excessive amount of a fungalpopulation is present in or on the person's body, or when the presenceof a fungal population(s) is damaging the cells or other tissue of theperson.

By “caprylocaproyl polyoxyglyceride” is meant a polyglycolized glyceridethat is a mixture of monoesters, diesters, and triesters of glycerol andmonoesters and diesters of polyethylene glycols having a mean molecularweight of between 70 and 400, and produced by transesterification ofcaprylic and capric glyceride esters with polyethylene glycol.Caprylocaproyl polyoxyglycerides include, without limitation,caprylic/capric PEG-8 glyceride (LABRASOL®, Gattefosse), caprylic/capricPEG-4 glyceride (LABRAFAC® Hydro, Gattefosse), and caprylic/capric PEG-6glyceride (SOFTIGEN®767, Huls).

By “effective” amount is meant the amount of drug required to treat orprevent an infection or a disease associated with an infection. Theeffective amount of drug used to practice the invention for therapeuticor prophylactic treatment of conditions caused by or contributed to by amicrobial infection varies depending upon the manner of administration,the age, body weight, and general health of the subject. Ultimately, theattending physician will decide the appropriate amount and dosageregimen. Such amount is referred to as an “effective” amount.

By “emulsion” is meant a two-phase colloidal system, such as a mixtureof two or more immiscible (unblendable) liquids. Liquid emulsions arethose in which both the dispersed and the continuous phases are liquid.Energy input through shaking, stirring, homogenizing, or spray processesare typically needed to form an emulsion. For example, the emulsion caninclude an aqueous phase and a nonaqueous phase, and can include a selfemulsifying system, or the emulsion can be nano particulate containingan aqueous phase and a nonaqueous phase (e.g., a nanoemulsion ormicroemulsion). By “microemulsion” is meant a clear, stable, isotropicliquid mixture of oil, water, and surfactant, optionally in combinationwith a cosurfactant. The aqueous phase may contain salt(s) and/or otheringredients in addition to a biologically active agent. In contrast toordinary emulsions, microemulsions form upon simple mixing of thecomponents and do not require the high shear conditions generally usedin the formation of ordinary emulsions. The two basic types ofmicroemulsions are direct (oil dispersed in water, o/w) and reversed(water dispersed in oil, w/o).

By “excipient” is meant those components of a pharmaceutical compositioncontaining a drug (e.g., an echinocandin class compound) in oral dosageform which do not increase the oral bioavailability of the drug whenorally administered simultaneously with the drug. Excipients which canbe used in the formulations of the invention include, withoutlimitation, water, diluents, binders, fillers, and flavorings.

By “fatty acid” is meant an aliphatic carboxylic acid. Fatty acidsinclude, but are not limited to, fatty acids having between 8 and 12carbon atoms, linear and branched fatty acids, saturated and unsaturatedfatty acids, and fatty acids having a hydroxyl group at the terminationposition of its side chain (i.e., fatty acids bearing a primary hydroxylgroup). Exemplary fatty acids are caprylic acid (octanoic acid),pelargonic acid (nonanoic acid), capric acid (decanoic acid), and lauricacid (dodecanoic acid), and their primary hydroxyl forms 8-hydroxyoctanoic acid, 9-hydroxy nonanoic acid, 10-hydroxy decanoic acid, and12-hydroxy dodecanoic acid.

By “hard capsule” is meant a capsule that includes a membrane that formsa two-part, capsule-shaped, container capable of carrying a solid,semi-solid, or liquid payload of drug, additive(s), and, optionally,excipients.

As used herein, by “increase the oral bioavailability” is meant at least25%, 50%, 75%, 100%, or 300% greater bioavailability of an orallyadministered drug, as a measured average of AUC in canine subjects(e.g., as described in the examples) for an oral dosage form of theinvention including an echinocandin class compound formulated with oneor more additives in comparison to the same drug formulated without anyadditives. For these studies the subjects have gastrointestinal tractsthat have not been surgically manipulated in a manner that would alterthe oral bioavailability of a drug.

By “liquid dosage form” is meant a solution or suspension from which adose is measured out (i.e., a teaspoon, tablespoon, or a number of cubiccentimeters) for oral administration to a subject.

By “loading-dose regimen” is meant a regimen for the administration ofechinocandin class compound that includes at least four administrationsof echinocandin class compound in which the dose level administered onDay 1 is at least 120%, 200%, 300%, 400%, or 500% of the dose leveladministered on any subsequent dosing days, corrected for differences inbioavailability using the formula: dose level=(% BA/100)×doseadministered, wherein % BA is percent bioavailability, which forintravenous and subcutaneous dosing is 100. For oral dosing the % BA isdetermined using method of Example 3. For intransal and othernon-injection routes of administration, the percent bioavailability canbe determined using analogous methods to those described in Example 3.By “dose level administered on Day 1” is meant the sum total of allechinocandin class compound administered to a subject over the first 24hours of the initial administration. By “dosing day” is meant a day onwhich an echinocandin class compound is administered to a subject andthe dose administered on a dosing day is the sum total of allechinocandin class compound administered over a 24 hour period beginningfrom the first administration on this day.

As used herein, “oral bioavailability” refers to the mean fraction ofdrug absorbed following oral administration to subjects as measured bythe blood circulating concentration in comparison to the bloodcirculating concentration observed for the 100% bioavailability observedwith intravenously or intraarterially administered drug. The oralbioavailability can be assessed for a particular formulation can beassessed as provided in Example 3.

By “polyglycolized glyceride” is meant a polyethylene glycol glyceridemonoester, a polyethylene glycol glyceride diester, a polyethyleneglycol glyceride triester, or a mixture thereof containing a variableamount of free polyethylene glycol, such as a polyethylene glycol-oiltransesterification product. The polyglycolized glyceride can includeeither monodisperse (i.e., single molecular weight) or polydispersepolyethylene glycol moieties of a predetermined size or size range(e.g., PEG2 to PEG 40). Polyethylene glycol glycerides include, forexample: PEG glyceryl caprate, PEG glyceryl caprylate, PEG-20 glyceryllaurate (TAGAT® L, Goldschmidt), PEG-30 glyceryl laurate (TAGAT® L2,Goldschmidt), PEG-15 glyceryl laurate (Glycerox L series, Croda), PEG-40glyceryl laurate (Glycerox L series, Croda), PEG-20 glyceryl stearate(CAPMUL® EMG, ABITEC), and ALDO® MS-20 KFG, Lonza), PEG-20 glyceryloleate (TAGAT® O, Goldschmidt), and PEG-30 glyceryl oleate (TAGAT® 02,Goldschmidt). Caprylocapryl PEG glycerides include, for example,caprylic/capric PEG-8 glyceride (LABRASOL®, Gattefosse), caprylic/capricPEG-4 glyceride (Labrafac® Hydro, Gattefosse), and caprylic/capric PEG-6glyceride (SOFTIGEN®767, Huls). Oleoyl PEG glyceride include, foreaxmaple oleoyl PEG-6 glyceride, (Labrafil M1944 CS, Gattefosee).Lauroyl PEG glycerides include, for example, lauroyl PEG-32 glyceride(GELUCIRE® ELUCIRE 44/14, Gattefosse). Stearoyl PEG glycerides include,for example stearoyl PEG-32 glyceride (Gelucrire 50/13, Gelucire 53/10,Gattefosse). PEG castor oils include PEG-3 castor oil (Nikkol CO-3,Nikko), PEG-5, 9, and 16 castor oil (ACCONON CA series, ABITEC), PEG-20castor oil, (Emalex C-20, Nihon Emulsion), PEG-23 castor oil (EmulganteEL23), PEG-30 castor oil (Incrocas 30, Croda), PEG-35 castor oil(Incrocas-35, Croda), PEG-38 castor oil (Emulgante EL 65, Condea),PEG-40 castor oil (Emalex C-40, Nihon Emulsion), PEG-50 castor oil(Emalex C-50, Nihon Emulsion), PEG-56 castor oil (EUMULGIN® PRT 56,Pulcra SA), PEG-60 castor oil (Nikkol CO-60TX, Nikko), PEG-100 castoroil, PEG-200 castor oil (EUMULGIN® PRT 200, Pulcra SA), PEG-5hydrogenated castor oil (Nikkol HCO-5, Nikko), PEG-7 hydrogenated castoroil (Cremophor W07, BASF), PEG-10 hydrogenated castor oil (NikkolHCO-10, Nikko), PEG-20 hydrogenated castor oil (Nikkol HCO-20, Nikko),PEG-25 hydrogenated castor oil (Simulsol® 1292, Seppic), PEG-30hydrogenated castor oil (Nikkol HCO-30, Nikko), PEG-40 hydrogenatedcastor oil (Cremophor RH 40, BASF), PEG-45 hydrogenated castor oil(Cerex ELS 450, Auschem Spa), PEG-50 hydrogenated castor oil (EmalexHC-50, Nihon Emulsion), PEG-60 hydrogenated castor oil (Nikkol HCO-60,Nikko), PEG-80 hydrogenated castor oil (Nikkol HCO-80, Nikko), andPEG-100 hydrogenated castor oil (Nikkol HCO-100, Nikko). Additionalpolyethylene glycol-oil transesterification products include, forexample, stearoyl PEG glyceride (GELUCIRE® 50/13, Gattefosse). Thepolyglycolized glycerides useful in the formulations of the inventioncan include polyethylene glycol glyceride monoesters, diesters, and/ortriesters of acetic, propionic, butyric, valeric, hexanoic, heptanoic,caprylic, nonanoic, capric, lauric, myristic, palmitic, heptadecanoic,stearic, arachidic, behenic, lignoceric, α-linolenic, stearidonic,eicosapentaenoic, docosahexaenoic, linoleic, γ-linolenic,dihomo-γ-linolenic, arachidonic, oleic, elaidic, eicosenoic, erucic, ornervonic acid, or mixtures thereof. The polyglycol moiety in apolyglycolized glyceride can be polydisperse; that is, they can have avariety of molecular weights.

As used herein, the term “salt” refers to any pharmaceuticallyacceptable salt, such as a non-toxic acid addition salt, metal salt, ormetal complex, commonly used in the pharmaceutical industry. Examples ofacid addition salts include organic acids, such as acetic, lactic,palmoic, maleic, citric, cholic acid, capric acid, caprylic acid, lauricacid, glutaric, glucuronic, glyceric, glycocolic, glyoxylic, isocitric,isovaleric, lactic, malic, oxalo acetic, oxalosuccinic, propionic,pyruvic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic,tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids,and inorganic acids, such as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid. Representative alkali or alkalineearth metal salts include sodium, lithium, potassium, calcium, andmagnesium, among others.

By “soft capsule” is meant a capsule molded into a single containercarrying a liquid payload of drug, additive(s), and, optionally,excipients.

By “subject” is meant an animal, e.g., a human, pet (e.g., dog or cat),farm animal (e.g., goat, cow, horse, sheep, or pig), and/or a mammal.

As used herein, the term “treating” refers to administering apharmaceutical composition for prophylactic and/or therapeutic purposes.To “prevent disease” refers to prophylactic treatment of a subject whois not yet ill, but who is susceptible to, or otherwise at risk of, aparticular disease. To “treat disease” or use for “therapeutictreatment” refers to administering treatment to a subject alreadysuffering from a disease to improve or stabilize the subject'scondition. Thus, in the claims and embodiments, treating is theadministration to a subject either for therapeutic or prophylacticpurposes.

The term “unit dosage form” refers to physically discrete units suitableas unitary dosages, such as a tablet, caplet, hard capsule, softcapsule, or sachet, each unit containing a predetermined quantity ofdrug.

In the generic descriptions of certain compounds, the number of atoms ofa particular type in a substituent group may be given as a range, e.g.,an alkyl group containing from 5 to 8 carbon atoms or C₅₋₈ alkyl.Reference to such a range is intended to include specific references togroups having each of the integer number of atoms within the specifiedrange. For example, an alkyl group from 5 to 8 carbon atoms includeseach of C₅, C₆, C₇, and C₈. A C₅₋₈ heteroalkyl, for example, includesfrom 5 to 8 carbon atoms in addition to one or more heteroatoms. Othernumbers of atoms and other types of atoms may be indicated in a similarmanner.

As used herein, the terms “alkyl” and the prefix “alk-” are inclusive ofboth straight chain and branched chain groups and of cyclic groups,i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic andpreferably have from 3 to 6 ring carbon atoms, inclusive. Exemplarycyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl groups. The C₁₋₈ alkyl group may be substituted orunsubstituted. Exemplary substituents include alkoxy, aryloxy,sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl,perfluoralkyl, cyano, nitrilo, NH-acyl, amino, aminoalkyl, disubstitutedamino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxylgroups.

By “C₂₋₁₀ heterocyclyl” is meant a stable 3- to 7-membered monocyclic or7- to 14-membered bicyclic heterocyclic ring which is saturatedpartially unsaturated or unsaturated (aromatic), and which consists of 2to 10 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selectedfrom the group consisting of N, O, and S and including any bicyclicgroup in which any of the above-defined heterocyclic rings is fused to abenzene ring. The heterocyclyl group may be substituted orunsubstituted. Exemplary substituents include alkoxy, aryloxy,sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl,perfluoralkyl, cyano, nitrilo, NH-acyl, amino, aminoalkyl, disubstitutedamino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxylgroups. The nitrogen and sulfur heteroatoms may optionally be oxidized.The heterocyclic ring may be covalently attached via any heteroatom orcarbon atom which results in a stable structure, e.g., an imidazolinylring may be linked at either of the ring-carbon atom positions or at thenitrogen atom. A nitrogen atom in the heterocycle may optionally bequaternized. Preferably when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother.

By “C₆₋₁₂ aryl” is meant an aromatic group having a ring systemcomprised of carbon atoms with conjugated π electrons (e.g., phenyl).The aryl group has from 6 to 12 carbon atoms. Aryl groups may optionallyinclude monocyclic, bicyclic, or tricyclic rings, in which each ringdesirably has five or six members. The aryl group may be substituted orunsubstituted. Exemplary subsituents are alkyl, hydroxy, alkoxy,aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl,hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino,disubstituted amino, and quaternary amino groups.

By “C₇₋₁₆ alkaryl” is meant an alkyl substituted by an aryl group (e.g.,benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 16 carbonatoms.

By “C₃₋₁₀ alkheterocyclyl” is meant an alkyl substituted heterocyclicgroup having from 3 to 10 carbon atoms in addition to one or moreheteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl,3-tetrahydrofuranylmethyl, or 2-tetrahydrofuranylmethyl).

Other features and advantages of the invention will be apparent from thefollowing detailed description, the drawings, and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-14 depict compounds of the invention.

FIGS. 15A and 15B are graphs depicting the stability of compound 22 andanidulafungin in various mammalian plasmas and phosphate buffered salineas described in Example 7. Compound 22 is more stable than anidulafunginin all of the matrices tested.

FIGS. 16A and 16B are graphs depicting the pharmacokinetic curvesobserved in chimpanzees for compound 22 and anidulafungin bothadministered intravenously (FIG. 16A) and for compound 22 administeredorally and anidulafungin administered intravenously (FIG. 16B).

FIGS. 17A-17C are graphs depicting the pharmacokinetic curves observedfor IV administered caspfungin (FIG. 17A, chimpanzee and man, see Hajduet al., Antimicrobial Agents and Chemotherapy, 41:2339 (1997)), IVadministered anidulafungin (FIG. 17B, chimpanzee and man, see CDERpackage submitted to the FDA for Eraxis), and IV administered compound22 (FIG. 17C, chimpanzee, see Example 8).

FIG. 18 is a graph depicting the pharmacokinetic curves observed inchimpanzees for compound 22 administered intravenously at 1 mg/kg andcompound 22 administered orally at 10 mg/kg.

FIG. 19 is a graph depicting the pharmacokinetic curves observed in ratsfor compound 22 administered intravenously and subcutaneously.

FIG. 20 is a graph depicting the pharmacokinetic curves observed inmonkeys for compound 22 administered intravenously and subcutaneously.

FIG. 21 is a graph depicting the calculated circulating concentrationsin human subjects for 200 mg compound 22 administered intravenously onceevery 7 days (solid line) and anidulafungin 200 mg administeredintravenously on day one, followed by 100 mg daily administeredintravenously (dotted line). The anidulafungin curve is based upon thecurves reported in the package insert for Eraxis. The curve for compound22 was calculated based upon a clearance of 3.4 mL/hr/kg and a plasmahalf life of 80 hr (values based upon chimpanzee studies).

FIG. 22 is a graph depicting the calculated circulating concentrationsin human subjects for 200 mg compound 22 administered intravenously onday one, followed by 500 mg daily oral administration (solid line), andanidulafungin 200 mg administered intravenously on day one, followed by100 mg daily administered intravenously (dotted line). The anidulafungincurve is based upon the curves reported in the package insert forEraxis. The curve for compound 22 was calculated based upon a clearanceof 3.4 mL/hr/kg, a plasma half life of 80 hr, and an oralbioavailability of 5% (values based upon chimpanzee studies).

DETAILED DESCRIPTION

The invention features dosing regimens and pharmaceutical formulationsfor oral administration including a drug (e.g., an echinocandin classcompound) formulated with a permeation enhancer. The formulations areuseful for increasing the oral bioavailability of the drug. Theinvention also features dosing regimens for echinocandin classcompounds, in particular compound 22, wherein the dosing frequency isreduced and/or the regimen permits self-administration (i.e.,subcutaneous or oral administration), such that the regimen can beperformed at least in part outside a hospital setting.

Echinocandin Class Compounds

The formulations of the invention can be used to increase the oralbioavailability of echinocandin class compounds. Echinocandin classcompounds are inhibitors of the synthesis of 1,3-β-D-glucan and includean antibiotic cyclic lipohexapeptide having the backbone depicted informula (I).

Echinocandin class compounds include, without limitation, caspofungin,echinocandin B, anidulafungin, pneumocandin B₀, aculeacin A_(γ),micafungin, and their derivatives.

Echinocandin class compounds can be synthesized, for example, bycoupling functionalized or unfunctionalized echinocandin class compoundswith the appropriate acyl, alkyl, hydroxyl, and/or amino groups understandard reaction conditions (see PCT Publication No. WO 2011/025875,and U.S. provisional Ser. No. 61/448,807, herein incorporated byreference). Typically, the semi-synthetic echinocandin class compoundsare made by modifying the naturally occurring echinocandin scaffold. Forexample, pneumocandin B₀ is prepared by fermentation reactions; wherefermentation and mixed broths produce a mixture of products which arethen separated to produce pneumocandin B₀, which is used in thesynthesis of caspofungin (see U.S. Pat. No. 6,610,822, which describesextractions of the echinocandin class compounds, such as, pneumocandinB₀, WF 11899 and echinocandin B by performing several extractionprocesses; and see U.S. Pat. No. 6,610,822, which describes methods forpurifying the crude extracts). For semi-synthetic approaches toechinocandin class compounds of the invention, the stereochemistry ofthe compound will be dictated by the starting material. Thus, thestereochemistry of the unnatural echinocandin derivatives will typicallyhave the same stereochemistry as the naturally occurring echinocandinscaffold from which they are derived. Accordingly, any of echinocandinB, anidulafungin, micafungin, and caspofungin, can be used as a startingmaterial in the synthesis of echinocandin class compounds which sharethe same stereochemical configuration at each of the amino acid residuesfound in the naturally occurring compound.

The echinocandin class compound can be selected from those described inPCT Publication No. WO 2011/025875, and U.S. provisional Ser. No.61/448,807, filed Mar. 3, 2011, each of are incorporated herein byreference.

The echinocandin class compound administered and/or formulated asdescribed herein can be a compound of formula (II):

In formula (II), R¹ is NHCH₂CH₂NHR^(A1), NHCH₂CH₂NR^(A1)R^(A2),NHCH₂CH₂NHC(O)R^(A1), CH₂NHR^(A1), CH₂NR^(A1)R^(A2), CH₂NHC(O)R^(A1), orOR^(A1); R² is H, CH₃, CH₂CH₂NHR^(B1), CH₂CH₂NR^(B1)R^(B2),CH₂CH₂NHC(O)R^(B1), CH₂C(O)NHR^(B1), CH₂CH₂CH(OR^(B1))NHR^(B2),CH₂CH₂CH(OR^(B1))NR^(B2)R^(B3), or CH₂CH₂CH(OR^(B1))NHC(O)R^(B2); R³ isH or CH₃; R⁴ is H, OSO₃H, CH₂NHR^(C1), CH₂NR^(C1)R^(C2),CH₂NHC(O)R^(C1); R⁵ is a lipophilic group selected from: PEG; C(O)-PEG;PEG-alkyl; C(O)-PEG-alkyl; PEG-aryl; C(O)-PEG-aryl; PEG-alkaryl;C(O)-PEG-alkaryl; alkyl-PEG; C(O)-alkyl-PEG; aryl-PEG; C(O)-aryl-PEG;alkaryl-PEG; C(O)-alkaryl-PEG;

each of R^(A1), R^(A2), R^(B1), R^(B2), R^(B3), R^(C1), and R^(C2) is,independently, selected from H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀alkheterocyclyl, C₁₋₁₀ heteroalkyl, PEG, alkyl-PEG, aryl-PEG,alkaryl-PEG, PEG-alkyl, PEG-aryl, and PEG-alkaryl, and pharmaceuticallyacceptable salts thereof, provided that the echinocandin class compoundincludes at least one PEG, alkyl-PEG, aryl-PEG, alkaryl-PEG, PEG-alkyl,PEG-aryl, or PEG-alkaryl group. In particular embodiments of theechinocandin class compound of formula (II), R⁴ is selected from: (i)—CH₂NH—(CH₂CH₂O)_(m)—(CH₂)_(n)-Me, (ii)—CH₂NH—(CH₂)_(q)—O—(CH₂CH₂O)_(m)-Me, (iii)—CH₂NH—(CH₂)_(p)—NH—(CO)—(CH₂)_(n)—O—(CH₂CH₂O)_(m)-Me, and (iv)—CH₂NHCH[(CH₂O(CH₂CH₂O)_(s)-Me)(CH₂O(CH₂CH₂O)_(t)-Me)], wherein n is aninteger from 0 to 11 (e.g., 0 to 7, 1 to 7, 2 to 7, 3 to 9, or 4 to 11),q is an integer from 3 to 12 (e.g., 3 to 7, 5 to 9, or 7 to 12), p is aninteger from 2 to 8 (e.g., 2 to 4, 3 to 6, or 4 to 8), s is an integerfrom 0 to 5 (e.g., 0, 1, 2, 3, 4, or 5), t is an integer from 0 to 5(e.g., 0, 1, 2, 3, 4, or 5), and m is an integer from 1 to 10 (e.g., 1to 7, 1 to 5, 2 to 7, 2 to 5, or 3 to 7). In still other embodiments ofthe echinocandin class compound of formula (II), R⁵ is selected from:(i) —(CH₂CH₂O)_(m)—(CH₂)_(n)-Me, (ii) —C(O)—(CH₂CH₂O)_(m)—(CH₂)_(n)-Me,(iii) —C(O)CH₂—O—(CH₂CH₂O)_(m)—(CH₂)_(n)-Me, and (iv)—C(O)—O—(CH₂CH₂O)_(m)—(CH₂)_(n)-Me, wherein n is an integer from 0 to 11(e.g., 0 to 7, 1 to 7, 2 to 7, 3 to 9, or 4 to 11), and m is an integerfrom 1 to 10 (e.g., 1 to 7, 1 to 5, 2 to 7, 2 to 5, or 3 to 7).

The echinocandin class compound administered and/or formulated asdescribed herein can be a compound of formula (III):

In formula (III), R^(1A) is H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀alkheterocyclyl, C₁₋₁₀ heteroalkyl, PEG, alkyl-PEG, aryl-PEG,alkaryl-PEG, PEG-alkyl, PEG-aryl, or PEG-alkaryl; R^(2A) is H, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl,C₇₋₁₄ alkaryl, C₃₋₁₀ alkheterocyclyl, C₁₋₁₀ heteroalkyl, PEG, alkyl-PEG,aryl-PEG, alkaryl-PEG, PEG-alkyl, PEG-aryl, or PEG-alkaryl; R⁴ is H,OSO₃H, CH₂NHR^(C1), CH₂NR^(C1)R^(C2), CH₂NHC(O)R^(C1); and each ofR^(C1) and R^(C2) is, independently, selected from H, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl,C₃₋₁₀ alkheterocyclyl, C₁₋₁₀ heteroalkyl, PEG, alkyl-PEG, aryl-PEG,alkaryl-PEG, PEG-alkyl, PEG-aryl, and PEG-alkaryl, and pharmaceuticallyacceptable salts thereof, provided that the echinocandin class compoundincludes at least one PEG, alkyl-PEG, aryl-PEG, alkaryl-PEG, PEG-alkyl,PEG-aryl, or PEG-alkaryl. In certain embodiments of the echinocandinclass compound of formula (III), one of R^(1A), R^(2A), R^(C1) andR^(C2) is selected from: (i) —(CH₂)_(p)—O—(CH₂CH₂O)_(m)-Me, and (ii)—(CH₂CH₂O)_(m)-Me, and (iii) —C(O)(CH₂)_(n)—(OCH₂CH₂)_(m)—OMe, wherein nis an integer from 0 to 11 (e.g., 0 to 7, 1 to 7, 2 to 7, 3 to 9, or 4to 11), p is an integer from 3 to 12 (e.g., 3 to 8, 4 to 10, or 6 to12), and m is an integer from 1 to 10 (e.g., 1 to 7, 1 to 5, 2 to 7, 2to 5, or 3 to 7). In particular embodiments of the echinocandin classcompound of formula (II), R^(1A) is H and R^(2A) is PEG, alkyl-PEG,aryl-PEG, alkaryl-PEG, PEG-alkyl, PEG-aryl, or PEG-alkaryl; R^(1A) isPEG, alkyl-PEG, aryl-PEG, alkaryl-PEG, PEG-alkyl, PEG-aryl, orPEG-alkaryl and R^(2A) is H; or each of R^(1A) and R^(2A) is,independently, selected from PEG, alkyl-PEG, aryl-PEG, alkaryl-PEG,PEG-alkyl, PEG-aryl, and PEG-alkaryl.

The echinocandin class compound administered and/or formulated asdescribed herein can be a compound of formula (IV):

In formula (IV), R¹ is NHCH₂CH₂NHR^(A1), NHCH₂CH₂NR^(A1)R^(A2),NHCH₂CH₂NHC(O)R^(A1), CH₂NHR^(A1), CH₂NR^(A1)R^(A2), CH₂NHC(O)R^(A1), orOR^(A1); R⁴ is H, OSO₃H, CH₂NHR^(C1), CH₂NR^(C1)R^(C2), CH₂NHC(O)R^(C1);and each of R^(A1), R^(A2), R^(C1), and R^(C2) is, independently,selected from H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkheterocyclyl, C₁₋₁₀heteroalkyl, PEG, alkyl-PEG, aryl-PEG, alkaryl-PEG, PEG-alkyl, PEG-aryl,and PEG-alkaryl, and pharmaceutically acceptable salts thereof, providedthat the echinocandin class compound includes at least one PEG,alkyl-PEG, aryl-PEG, alkaryl-PEG, PEG-alkyl, PEG-aryl, or PEG-alkarylgroup. In certain embodiments of the echinocandin class compound offormula (IV), R¹ is selected from: (i) —O—(CH₂CH₂O)_(m)—(CH₂)_(n)-Me,(ii) —NH—(CH₂CH₂O)_(m)—(CH₂)_(n)-Me, (iii)—O—(CH₂)_(q)—O—(CH₂CH₂O)_(m)-Me, (iv) —NH—(CH₂)_(q)—O—(CH₂CH₂O)_(m)-Me,(v) —O—(CH₂)_(p)—NH—(CO)—(CH₂)_(n)—O—(CH₂CH₂O)_(m)-Me, (vi)—NH—(CH₂)_(p)—NH—(CO)—(CH₂)_(n)—O—(CH₂CH₂O)_(m)-Me, (vii)—NHCH[(CH₂O(CH₂CH₂O)_(s)-Me)(CH₂O(CH₂CH₂O)_(t)-Me)], and (viii)—O—CH[(CH₂O(CH₂CH₂O)_(s)-Me)(CH₂O(CH₂CH₂O)_(t)-Me)], wherein n is aninteger from 0 to 11 (e.g., 0 to 7, 1 to 7, 2 to 7, 3 to 9, or 4 to 11),q is an integer from 3 to 12 (e.g., 3 to 7, 5 to 9, or 7 to 12), p is aninteger from 2 to 8 (e.g., 2 to 4, 3 to 6, or 4 to 8), s is an integerfrom 0 to 5 (e.g., 0, 1, 2, 3, 4, or 5), t is an integer from 0 to 5(e.g., 0, 1, 2, 3, 4, or 5), and m is an integer from 1 to 10 (e.g., 1to 7, 1 to 5, 2 to 7, 2 to 5, or 3 to 7).

The echinocandin class compound administered and/or formulated asdescribed herein can be a compound of formula (V):

In formula (V), R¹ is NHCH₂CH₂NHR^(A1), NHCH₂CH₂NR^(A1)R^(A2),NHCH₂CH₂NHC(O)R^(A1), CH₂NHR^(A1), CH₂NR^(A1)R^(A2), CH₂NHC(O)R^(A1), orOR^(A1); R² is H, CH₃, CH₂CH₂NHR^(B1), CH₂CH₂NR^(B1)R^(B2),CH₂CH₂NHC(O)R^(B1), CH₂C(O)NHR^(B1), CH₂CH₂CH(OR^(B1))NHR^(B2),CH₂CH₂CH(OR^(B1))NR^(B2)R^(B3), or CH₂CH₂CH(OR^(B1))NHC(O)R^(B2); R⁴ isH, OSO₃H, CH₂NHR^(C1), CH₂NR^(C1)R^(C2), CH₂NHC(O)R^(C1); and each ofR^(A1), R^(A2), R^(B1), R^(B2), R^(C1), and R^(C2) is, independently,selected from H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkheterocyclyl, C₁₋₁₀heteroalkyl, PEG, alkyl-PEG, aryl-PEG, alkaryl-PEG, PEG-alkyl, PEG-aryl,and PEG-alkaryl, and pharmaceutically acceptable salts thereof, providedthat the echinocandin class compound includes at least one PEG,alkyl-PEG, aryl-PEG, alkaryl-PEG, PEG-alkyl, PEG-aryl, or PEG-alkarylgroup. In certain embodiments of the echinocandin class compound offormula (V), R¹ is selected from: (i) —O—(CH₂CH₂O)_(m)—(CH₂)_(n)-Me,(ii) —NH—(CH₂CH₂O)_(m)—(CH₂)_(n)-Me, (iii)—O—(CH₂)_(q)—O—(CH₂CH₂O)_(m)-Me, (iv) —NH—(CH₂)_(q)—O—(CH₂CH₂O)_(m)-Me,(v) —O—(CH₂)_(p)—NH—(CO)—(CH₂)_(n)—O—(CH₂CH₂O)_(m)-Me, (vi)—NH—(CH₂)_(p)—NH—(CO)—(CH₂)_(n)—O—(CH₂CH₂O)_(m)-Me, (vii)—NHCH[(CH₂O(CH₂CH₂O)_(s)-Me)(CH₂O(CH₂CH₂O)_(t)-Me)], and (viii)—O—CH[(CH₂O(CH₂CH₂O)₅-Me)(CH₂O(CH₂CH₂O)_(t)-Me)], wherein n is aninteger from 0 to 11 (e.g., 0 to 7, 1 to 7, 2 to 7, 3 to 9, or 4 to 11),q is an integer from 3 to 12 (e.g., 3 to 7, 5 to 9, or 7 to 12), p is aninteger from 2 to 8 (e.g., 2 to 4, 3 to 6, or 4 to 8), s is an integerfrom 0 to 5 (e.g., 0, 1, 2, 3, 4, or 5), t is an integer from 0 to 5(e.g., 0, 1, 2, 3, 4, or 5), and m is an integer from 1 to 10 (e.g., 1to 7, 1 to 5, 2 to 7, 2 to 5, or 3 to 7).

The echinocandin class compound administered and/or formulated asdescribed herein can be a compound of formula (VI):

In formula (VI), R¹ is NHCH₂CH₂NHR^(A1), NHCH₂CH₂NR^(A1)R^(A2),NHCH₂CH₂NHC(O)R^(A1), CH₂NHR^(A1), CH₂NR^(A1)R^(A2), CH₂NHC(O)R^(A1), orOR^(A1); R² is H, CH₃, CH₂CH₂NHR^(B1), CH₂CH₂NR^(B1)R^(B2),CH₂CH₂NHC(O)R^(B1), CH₂C(O)NHR^(B1), CH₂CH₂CH(OR^(B1))NHR^(B2),CH₂CH₂CH(OR^(B1))NR^(B2)R^(B3), or CH₂CH₂CH(OR^(B1))NHC(O)R^(B2); andeach of R^(A1), R^(A2), R^(B1), R^(B2), and R^(B3) is, independently,selected from H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkheterocyclyl, C₁₋₁₀heteroalkyl, PEG, alkyl-PEG, aryl-PEG, alkaryl-PEG, PEG-alkyl, PEG-aryl,and PEG-alkaryl, and pharmaceutically acceptable salts thereof, providedthat the echinocandin class compound includes at least one PEG,alkyl-PEG, aryl-PEG, alkaryl-PEG, PEG-alkyl, PEG-aryl, or PEG-alkarylgroup. In certain embodiments of the echinocandin class compound offormula (VI), R¹ is selected from: (i) —O—(CH₂CH₂O)_(m)—(CH₂)_(n)-Me,(ii) —NH—(CH₂CH₂O)_(m)—(CH₂)_(n)-Me, (iii)—O—(CH₂)_(q)—O—(CH₂CH₂O)_(m)-Me, (iv) —NH—(CH₂)_(q)—O—(CH₂CH₂O)_(m)-Me,(v) —O—(CH₂)_(p)—NH—(CO)—(CH₂)_(n)—O—(CH₂CH₂O)_(m)-Me, (vi)—NH—(CH₂)_(p)—NH—(CO)—(CH₂)_(n)—O—(CH₂CH₂O)_(m)-Me, (vii)—NHCH[(CH₂O(CH₂CH₂O)_(s)-Me)(CH₂O(CH₂CH₂O)_(t)-Me)], and (viii)—O—CH[(CH₂O(CH₂CH₂O)_(s)-Me)(CH₂O(CH₂CH₂O)_(t)-Me)], wherein n is aninteger from 0 to 11 (e.g., 0 to 7, 1 to 7, 2 to 7, 3 to 9, or 4 to 11),q is an integer from 3 to 12 (e.g., 3 to 7, 5 to 9, or 7 to 12), p is aninteger from 2 to 8 (e.g., 2 to 4, 3 to 6, or 4 to 8), s is an integerfrom 0 to 5 (e.g., 0, 1, 2, 3, 4, or 5), t is an integer from 0 to 5(e.g., 0, 1, 2, 3, 4, or 5), and m is an integer from 1 to 10 (e.g., 1to 7, 1 to 5, 2 to 7, 2 to 5, or 3 to 7).

The echinocandin class compound administered and/or formulated asdescribed herein can be a compound of formula (VII):

In formula (VII), R¹ is O(CH₂CH₂O)_(n)CH₂CH₂X₁,O(CH₂CH₂CH₂O)_(n)CH₂CH₂X₁, NHCH₂CH₂X₂, NH(CH₂CH₂O)_(m)CH₂CH₂X₂,NH(CH₂CH₂CH₂O)_(m)CH₂CH₂X₂, NH(CH₂CH₂O)_(p)CH₂CH₂X₃,NH(CH₂CH₂CH₂O)_(p)CH₂CH₂X₃, NHCH₂CH₂X₄,NH[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₅}₂,O[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₅}₂,NH(CH₂CH₂NH)_(r)CH₂CH₂X₅, NHCH₂(CH₂)_(q)X₆, or OCH₂(CH₂)_(q)X₆; R^(T) isn-pentyl, sec-pentyl, or iso-pentyl; X₁ is NH₂, NHR^(A1), NR^(A1)R^(A2),NR^(A1)R^(A2)R^(A3), or NHCH₂(CH₂)_(v)Z₁; X₂ is OH, OR^(B1), orOCH₂(CH₂)_(v)Z₁; X₃ is NH₂, NHR^(C1), NR^(C1)R^(C2), orNR^(C1)R^(C2)R^(C3), or NHCH₂(CH₂)_(v)Z₁; X₄ is NR^(D1)R^(D2)R^(D3) orNHCH₂(CH₂)_(v)Z₁; each X₅ is, independently, selected from OH, OR^(E1),NH₂, NHR^(E1), NR^(E1)R^(E2), NR^(E1)R^(E2)R^(E3), OCH₂(CH₂)_(v)Z₁, andNHCH₂(CH₂)_(v)Z₁; X₆ is selected from NR^(F1)R^(F2)R^(F3) or Z₁; a is aninteger from 1 to 2; b is an integer from 0 to 3 (e.g., 0, 1, 2, or 3);c is an integer from 1 to 2; d is an integer from 0 to 3 (e.g., 0, 1, 2,or 3); n is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5); m is aninteger from 1 to 5 (e.g., 1, 2, 3, 4, or 5); p is an integer from 1 to5 (e.g., 1, 2, 3, 4, or 5); r is an integer from 1 to 5 (e.g., 1, 2, 3,4, or 5); q is an integer from 1 to 3 (e.g., 1, 2, or 3); v is aninteger from 1 to 3 (e.g., 1, 2, or 3); each of R^(A1), R^(A2), R^(A3),R^(B1), R^(C1), R^(C2), R^(C3), R^(D1), R^(D2), R^(D3), R^(E1), R^(E2),R^(E3), R^(F1), R^(F2), and R^(F3) is, independently, selected from CH₃,CH₂CH₃, CH₂CH₂CH₃, and CH(CH₃)₂; Z₁ is selected from:

and each of R^(1A), R^(2A), R^(3A), R^(4A), R^(5A), R^(6A), R^(7A),R^(8A), R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(14A), R^(15A),R^(16A), R^(17A), R^(18A), R^(19A), R^(20A), R^(21A), and R^(22A) is,independently, selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, and CH(CH₃)₂, ora pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula (VII) is furtherdescribed by formula (VIIa):

In formula (VIIa), R¹ is O(CH₂CH₂O)_(n)CH₂CH₂X₁,O(CH₂CH₂CH₂O)_(n)CH₂CH₂X₁, NHCH₂CH₂X₂, NH(CH₂CH₂O)_(m)CH₂CH₂X₂,NH(CH₂CH₂CH₂O)_(m)CH₂CH₂X₂, NH(CH₂CH₂O)_(p)CH₂CH₂X₃,NH(CH₂CH₂CH₂O)_(p)CH₂CH₂X₃, NHCH₂CH₂X₄,NH[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₅}₂,O[CH₂(CH₂)_(a)]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₅}₂,NH(CH₂CH₂NH)_(r)CH₂CH₂X₅, NHCH₂(CH₂)_(q)X₆, or OCH₂(CH₂)_(q)X₆; R^(T) isn-pentyl, sec-pentyl, or iso-pentyl; X₁ is NH₂, NHR^(A1), NR^(A1)R^(A2),or NR^(A1)R^(A2)R^(A3); X₂ is OH or OR^(B1); X₃ is NH₂, NHR^(C1),NR^(C1)R^(C2), or NR^(C1)R^(C2)R^(C3); X₄ is NR^(D1)R^(D2)R^(D3); eachX₅ is, independently, selected from OH, OR^(E1), NH₂, NHR^(E1),NR^(E1)R^(E2), and NR^(E1)R^(E2)R^(E3); X₆ is selected fromNR^(F1)R^(F2)R^(F3); a is an integer from 1 to 2; b is an integer from 0to 3 (e.g., 0, 1, 2, or 3); c is an integer from 1 to 2; d is an integerfrom 0 to 3 (e.g., 0, 1, 2, or 3); n is an integer from 1 to 5 (e.g., 1,2, 3, 4, or 5); m is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5); pis an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5); r is an integer from1 to 5 (e.g., 1, 2, 3, 4, or 5); q is an integer from 1 to 3 (e.g., 1,2, or 3); and each of R^(A1), R^(A2), R^(A3), R^(B1), R^(C1), R^(C2),R^(C3), R^(D1), R^(D2), R^(D3), R^(E1), R^(E2), R^(E3), R^(F1), R^(F2),and R^(F3) is, independently, selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, andCH(CH₃)₂, or a pharmaceutically acceptable salt thereof. In particularembodiments of the compounds of formula (I) and (Ia), one of X₁, X₃, X₄,and X₅ is selected from N(CH₃)₃ ⁺ and N(CH₂CH₃)₃ ⁺. In certainembodiments of the compounds of formula (I) and (Ia), R¹ isNHCH[CH₂CH₂N(CH₃)₃ ⁺]₂, NHCH₂CH₂OCH[CH₂CH₂N(CH₃)₃ ⁺]₂, orNHCH₂CH₂OCH[CH₂CH₂N(CH₃)₃ ⁺][CH₂CH₂OCH₂CH₂OH].

In still other embodiments, the compound of formula (VII) is furtherdescribed by formula (VIIb):

In formula (VIIb), R¹ is O(CH₂CH₂O)_(n)CH₂CH₂X₁,O(CH₂CH₂CH₂O)_(n)CH₂CH₂X₁, NHCH₂CH₂X₂, NH(CH₂CH₂O)_(m)CH₂CH₂X₂,NH(CH₂CH₂CH₂O)_(m)CH₂CH₂X₂, NH(CH₂CH₂O)_(p)CH₂CH₂X₃,NH(CH₂CH₂CH₂O)_(p)CH₂CH₂X₃, NHCH₂CH₂X₄,NH[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₅}₂,O[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₅}₂,NH(CH₂CH₂NH)_(r)CH₂CH₂X₅, NHCH₂(CH₂)_(q)X₆, or OCH₂(CH₂)_(q)X₆; R^(T) isn-pentyl, sec-pentyl, or iso-pentyl; X₁ is NHCH₂(CH₂)_(v)Z₁; X₂ isOCH₂(CH₂)_(v)Z₁; X₃ is NHCH₂(CH₂)_(v)Z₁; X₄ is NHCH₂(CH₂)_(v)Z₁; each X₅is, independently, selected from OCH₂(CH₂)_(v)Z₁ and NHCH₂(CH₂)_(v)Z₁;X₆ is Z₁; a is an integer from 1 to 2; b is an integer from 0 to 3(e.g., 0, 1, 2, or 3); c is an integer from 1 to 2; d is an integer from0 to 3 (e.g., 0, 1, 2, or 3); n is an integer from 1 to 5 (e.g., 1, 2,3, 4, or 5); m is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5); p isan integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5); r is an integer from 1to 5 (e.g., 1, 2, 3, 4, or 5); q is an integer from 1 to 3 (e.g., 1, 2,or 3); v is an integer from 1 to 3 (e.g., 1, 2, or 3); Z₁ is selectedfrom:

and each of R^(1A), R^(2A), R^(3A), R^(4A), R^(5A), R^(6A), R^(7A),R^(8A), R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(14A), R^(15A),R^(16A), R^(17A), R^(18A), R^(19A), R^(20A), R^(21A), and R^(22A) is,independently, selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, and CH(CH₃)₂, ora pharmaceutically acceptable salt thereof.

In one particular embodiment of the compounds of formula (VII), (VIIa),and (VIIb), the compound is further described by one of the formulas:

wherein R¹ and R^(T) are as described in formula (VII).

The echinocandin class compound administered and/or formulated asdescribed herein can be a compound of formula (VIII):

In formula (VIII), R² is NH(CH₂CH₂O)_(s)CH₂CH₂X₈,NH(CH₂CH₂CH₂O)_(s)CH₂CH₂X₈, NH(CH₂CH₂NH)_(t)CH₂CH₂X₉,NH[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₉}₂,O[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₉}₂, NHCH₂(CH₂)_(u)X₁₀, orOCH₂(CH₂)_(u)X₁₀; X₈ is OH, OR^(G1), NH₂, NHR^(G1), NR^(G1)R^(G2),NR^(G1)R^(G2)R^(G3), OCH₂(CH₂)_(w)Z₂, or NHCH₂(CH₂)_(v)Z₂; each X₉ is,independently, selected from OH, OR^(H1), NHR^(H1), NR^(H1)R^(H2),NR^(H1)R^(H2)R^(H3), OCH₂(CH₂)_(w)Z₂, and NHCH₂(CH₂)_(v)Z₂; X₁₀ isselected from NR^(I1)R^(I2)R^(I3) or Z₂; a is an integer from 1 to 2; bis an integer from 0 to 3 (e.g., 0, 1, 2, or 3); c is an integer from 1to 2; d is an integer from 0 to 3 (e.g., 0, 1, 2, or 3); s is an integerfrom 1 to 5 (e.g., 1, 2, 3, 4, or 5); t is an integer from 1 to 5 (e.g.,1, 2, 3, 4, or 5); u is an integer from 1 to 3 (e.g., 1, 2, or 3); eachof R^(G1), R^(G2), R^(G3), R^(H1), R^(H2), R^(H3), R^(I1), R^(I2), andR^(I3) is, independently, selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, andCH(CH₃)₂; w is an integer from 1 to 3 (e.g., 1, 2, or 3); Z₂ is selectedfrom

and each of R^(1A), R^(2A), R^(3A), R^(4A), R^(5A), R^(6A), R^(7A),R^(8A), R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(14A), R^(15A),R^(16A), R^(17A), R^(18A), R^(19A), R^(20A), R^(21A), and R^(22A) is,independently, selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, and CH(CH₃)₂, ora pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula (VIII) is furtherdescribed by formula (VIIIa):

In formula (VIIIa), R² is NH(CH₂CH₂O)_(s)CH₂CH₂X₈,NH(CH₂CH₂CH₂O)_(s)CH₂CH₂X₈, NH(CH₂CH₂NH)_(t)CH₂CH₂X₉,NH[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₉}₂,O[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₉}₂, NHCH₂(CH₂)_(u)X₁₀, orOCH₂(CH₂)_(u)X₁₀; X₈ is OH, OR^(G1), NH₂, NHR^(G1), NR^(G1)R^(G2), orNR^(G1)R^(G2)R^(G3); each X₉ is, independently, selected from OH,OR^(H1), NHR^(H1), NR^(H1)R^(H2), and NR^(H1)R^(H1)R^(H2)R^(H3); X₁₀ isselected from NR^(I1)R^(I2)R^(I3); a is an integer from 1 to 2; b is aninteger from 0 to 3 (e.g., 0, 1, 2, or 3); c is an integer from 1 to 2;d is an integer from 0 to 3 (e.g., 0, 1, 2, or 3); s is an integer from1 to 5 (e.g., 1, 2, 3, 4, or 5); t is an integer from 1 to 5 (e.g., 1,2, 3, 4, or 5); u is an integer from 1 to 3 (e.g., 1, 2, or 3); and eachof R^(G1), R^(G2), R^(G3), R^(H1), R^(H2), R^(H3), R^(I1), R^(I2), andR^(I3) is, independently, selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, andCH(CH₃)₂, or a pharmaceutically acceptable salt thereof. In particularembodiments of the compounds of formula (II) and (IIa), one of X₈ and X₉is selected from N(CH₃)₃ ⁺ and N(CH₂CH₃)₃ ⁺. In certain embodiments ofthe compounds of formula (II) and (IIa), R² is NHCH[CH₂CH₂N(CH₃)₃ ⁺]₂,NHCH₂CH₂OCH[CH₂CH₂N(CH₃)₃ ⁺]₂, or NHCH₂CH₂OCH[CH₂CH₂N(CH₃)₃⁺][CH₂CH₂OCH₂CH₂OH].

In still other embodiments, the compound of formula (I) is furtherdescribed by formula (VIIIb):

In formula (VIIIb), R² is NH(CH₂CH₂O)_(s)CH₂CH₂X₈,NH(CH₂CH₂CH₂O)_(s)CH₂CH₂X₈, NH(CH₂CH₂NH)_(t)CH₂CH₂X₉,NH[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₉}₂,O[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₉}₂, NHCH₂(CH₂)_(u)X₁₀, orOCH₂(CH₂)_(u)X₁₀; X₈ is OCH₂(CH₂)_(w)Z₂ or NHCH₂(CH₂)_(v)Z₂; each X₅ is,independently, selected from OCH₂(CH₂)_(w)Z₂ and NHCH₂(CH₂)_(v)Z₂; X₁₀is Z₂; a is an integer from 1 to 2; b is an integer from 0 to 3 (e.g.,0, 1, 2, or 3); c is an integer from 1 to 2; d is an integer from 0 to 3(e.g., 0, 1, 2, or 3); s is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or5); t is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5); u is aninteger from 1 to 3 (e.g., 1, 2, or 3); w is an integer from 1 to 3(e.g., 1, 2, or 3); Z₂ is selected from

and each of R^(1A), R^(2A), R^(3A), R^(4A), R^(5A), R^(6A), R^(7A),R^(8A), R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(14A), R^(15A),R^(16A), R^(17A), R^(18A), R^(19A), R^(20A), R^(21A), and R^(22A) is,independently, selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, and CH(CH₃)₂, ora pharmaceutically acceptable salt thereof.

In one particular embodiment of the compounds of formula (VIII),(VIIIa), and (VIIIb), the compound is further described by one of theformulas:

wherein R² is as described in formula (VIII).

The echinocandin class compound administered and/or formulated asdescribed herein can be a compound of formula (IX):

In formula (IX), R¹ is O(CH₂CH₂O)_(n)CH₂CH₂X₁, O(CH₂CH₂CH₂O), CH₂CH₂X₁,NHCH₂CH₂X₂, NH(CH₂CH₂O)_(m)CH₂CH₂X₂, NH(CH₂CH₂CH₂O)_(m)CH₂CH₂X₂,NH(CH₂CH₂O)_(p)CH₂CH₂X₃, NH(CH₂CH₂CH₂O)_(p)CH₂CH₂X₃, NHCH₂CH₂X₄,NH[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₅}₂,O[CH₂(CH₂)_(a)O]_(b)CH{CH₂[OCH₂(CH₂)_(c)]_(d)X₅}₂,NH(CH₂CH₂NH)_(r)CH₂CH₂X₅, NHCH₂(CH₂)_(q)X₆, or OCH₂(CH₂)_(q)X₆; R² is H,CH₃, CH₂CH₂NH₂, or CH₂C(O)NH₂; R^(T) is n-pentyl, sec-pentyl, oriso-pentyl; X₁ is NH₂, NHR^(A1), NR^(A1)R^(A2), NR^(A1)R^(A2)R^(A3), orNHCH₂(CH₂)_(v)Z₁; X₂ is OH, OR^(B1), or OCH₂(CH₂)_(v)Z₁; X₃ is NH₂,NHR^(C1), NR^(C1)R^(C2), or NR^(C1)R^(C2)R^(C3), or NHCH₂(CH₂)_(v)Z₁; X₄is NR^(D1)R^(D2)R^(D3) or NHCH₂(CH₂)_(v)Z₁; each X₅ is, independently,selected from OH, OR^(E1), NH₂, NHR^(E1), NR^(E1)R^(E2),NR^(E1)R^(E2)R^(E3), OCH₂(CH₂)_(v)Z₁, and NHCH₂(CH₂)_(v)Z₁; X₆ isselected from NR^(E1)R^(E2)R^(E3) or Z₁; a is an integer from 1 to 2; bis an integer from 0 to 3 (e.g., 0, 1, 2, or 3); c is an integer from 1to 2; d is an integer from 0 to 3 (e.g., 0, 1, 2, or 3); n is an integerfrom 1 to 5 (e.g., 1, 2, 3, 4, or 5); m is an integer from 1 to 5 (e.g.,1, 2, 3, 4, or 5); p is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5);r is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5); q is an integerfrom 1 to 3 (e.g., 1, 2, or 3); v is an integer from 1 to 3 (e.g., 1, 2,or 3); each of R^(A1), R^(A2), R^(A3), R^(B1), R^(C1), R^(C2), R^(C3),R^(D1), R^(D2), R^(D3), R^(E1), R^(E2), R^(E3), R^(F1), R^(F2), andR^(F3) is, independently, selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, andCH(CH₃)₂; Z₁ is selected from:

and each of R^(1A), R^(2A), R^(3A), R^(4A), R^(5A), R^(6A), R^(7A),R^(8A), R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(14A), R^(15A),R^(16A), R^(17A), R^(18A), R^(19A), R^(20A), R^(21A), and R^(22A) is,independently, selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, and CH(CH₃)₂, ora pharmaceutically acceptable salt thereof. In particular embodiments ofthe compounds of formula (IX), one of X₁, X₃, X₄, X₅, and X₆ is selectedfrom N(CH₃)₃ ⁺ and N(CH₂CH₃)₃ ⁺.

In one particular embodiment of the compounds of formula (IX), thecompound is further described by one of the formulas:

wherein R¹, R², and R^(T) are as described in formula (IX).

Any of compounds 1-46 (depicted in FIGS. 1-14), or a pharmaceuticallyacceptable salt thereof, can be used in the methods and compositions ofthe invention.

Oral Dosage Formulations

The present invention features oral dosage formulations having additivesincluding acyl carnitines, alkyl saccharides, ester saccharides, amidofatty acids, ammonium sulfonate surfactants, bile acids and salts(including cholic acid and salts thereof), chitosan and derivativesthereof, fatty acids and salts or esters thereof, glycerides,hydrophilic aromatic alcohols, pegylated phospholipids, peptideepithelial tight junction modulators, phospholipids, polyethylene glycolalkyl ethers, polyglycolized glycerides, polyglycerol fatty acid esters,polysorbate surfactants, carboxylic acids, polyethylene glycols, or amixture thereof. These additives can increase the oral bioavailabilityof echinocandin class compounds, and pharmaceutically acceptable saltsthereof.

Acyl Carnitines

Acyl carnitines can be used in the oral dosage forms of the invention,in either their zwitter ion form or salt form. Acyl carnitines can bederived carnitine (D or L form, or a mixture thereof) and a fatty acidincluding, without limitation, fatty acids having 16 carbon atoms and 0,1 or 2 double bonds (C16:0; C16:1 and C16:2), those with 18 carbon atomsand 1, 2 or 3 double bonds (C18:1; C18:2; and C18:3), those with 20carbon atoms and 1, 2 or 4 double bonds (C20:1; C20:2; and C20:4) andthose with 22 carbon atoms and 4, 5 or 6 double bonds (C22:4; C22:5 andC22:6). Exemplary acyl carnitines which are useful additives in theformulations of the invention include oleoyl carnitine, palmitoylcarnitine, decanoyl carnitine, dodecanoyl carnitine, myristoylcarnitine, and stearoyl carnitine.

Alkyl Saccharides

Alkyl saccharides can be used in the oral dosage forms of the invention.Alkyl saccharides are sugar ethers of a hydrophobic alkyl group (e.g.,typically from 9 to 24 carbon atoms in length). Alkyl saccharidesinclude alkyl glycosides and alkyl glucosides. In particularembodiments, the echinocandin class compound is formulated with a C₈₋₁₄alkyl ether of a sugar. Alkyl glycosides that can be used in the oraldosage forms of the invention include, without limitation, C₈₋₁₄ alkyl(e.g., octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, ortetradecyl-) ethers of α or β-D-maltoside, -glucoside or -sucroside,alkyl thiomaltosides, such as heptyl, octyl, dodecyl-, tridecyl-, andtetradecyl-β-D-thiomaltoside; alkyl thioglucosides, such as heptyl- oroctyl 1-thio α- or β-D-glucopyranoside; alkyl thiosucroses; and alkylmaltotriosides. For example, the echinocandin class compound can beformulated with octyl maltoside, dodecyl maltoside, tridecyl maltoside,or tetradecyl maltoside. Alkyl glucosides that can be used in the oraldosage forms of the invention include, without limitation, C₈₋₁₄ alkyl(e.g., octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, ortetradecyl-) ethers of glucoside, such as dodecyl glucoside or decylglucoside.

Amido Fatty Acids

Amido fatty acids can be used in the oral dosage forms of the invention.Amido fatty acids are long chain amino acid amides of formula (A), andsalts thereof:

In formula (A), k is an integer from 1 to 10 and R* is C₅₋₈ alkyl, C₆₋₁₂aryl, C₇₋₁₆ alkaryl, C₃₋₁₀ alkheterocyclyl, and C₂₋₁₀ heterocyclyl.Amido fatty acids include those described in U.S. Pat. Nos. 5,650,386and 8,110,547, each of which is incorporated herein by reference. Inparticular embodiments, k is an integer from 1 to 7 and R* is C₆₋₁₂ arylor C₇₋₁₆ alkaryl. Exemplary amido fatty acids which are useful additivesin the formulations of the invention include (i)N-[8-(2-hydroxybenzoyl)amino]caprylic acid (also known as “NAC”), andsalts thereof, including its sodium salt (also known as “SNAC”); (ii)8-(N-2-hydroxy-4-methoxybenzoyl)-aminocaprylic acid (also known as“4-MOAC”), and salts thereof, including its sodium salt; (iii)N-(8-[2-hydroxybenzoyl]-amino)decanoic acid (also known as “NAD”), andsalts thereof, including its sodium salt (also known as “SNAD”); (iv)N-(8-[2-hydroxy-5-chlorobenzoyl]-amino)octanoic acid (also known as“5-CNAC”), and salts thereof, including its sodium salt; and (iv)4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate (also known as “4-CNAB”),and salts thereof, including its sodium salt.

Ammonium Sulfonate Surfactants

Ammonium sulfonate surfactants can be used in the oral dosage forms ofthe invention. Ammonium sulfonate surfactants are zwitterionic additivesof formula (B):

In formula (B), m is an integer from 0 to 3, each of R^(B1) and R^(B2)are, independently, selected from methyl, ethyl, and propyl; and R^(B3)is a saturated or unsaturated alkyl of 6 to 18 carbons in length.Exemplary ammonium sulfonate surfactants which can be useful additivesin the formulations of the invention includeN-alkyl-N,N-dimethylammonio-1-propanesulfonates, such asdimethylpalmityl-amino propanesulfonate (DPPS).

Bile Acids and Salts

Bile acids and salts can be used in the oral dosage forms of theinvention. For example, the formulations can include, withoutlimitation, bile acids and salts such as sodium cholate, sodiumglycocholate, sodium glycodeoxycholate, taurodeoxycholate, sodiumdeoxycholate, sodium taurodihydrofusidate, taurocholate, andursodeoxycholate, sodium lithocholate, chenocholate, chenodeoxycholate,ursocholate, ursodeoxycholate, hyodeoxycholate, dehydrocholate,glycochenocholate, taurochenocholate, taurochenodeoxycholate, or theircorresponding acids.

Chitosan and Derivatives Thereof

Chitosan and derivatives thereof can be used in the oral dosage forms ofthe invention. Chitosan is prepared by the deacetylation of chitin. Foruse in the formulations of the invention, the degree of deacetylation,which represents the proportion of N-acetyl groups which have beenremoved through deacetylation, should be in the range of from about 40to about 100%, (e.g., 60 to about 96% or 70 to 95%). Desirably, thechitosan, or chitosan derivative, should have a molecular weight of fromabout 3,000 to about 1,000,000 Da (e.g., from about 10,000 to about800,000 Da, from about 15,000 to about 600,000 Da, or from 30,000 or50,000 to about 600,000 Da). Chitosan derivatives includepharmaceutically acceptable organic and inorganic salts (e.g., nitrate,phosphate, acetate, hydrochloride, lactate, citrate and glutamate salts,among others). Chitosan derivatives can be prepared by bonding moietiesto the hydroxyl or amino groups of chitosan and may confer the polymerwith changes in properties such as solubility characteristics and chargedensity. Examples include O-alkyl ethers of chitosan and O-acyl estersof chitosan. Other examples of chitosan derivatives includecarboxymethyl chitosan (see Thanou et al, J. Pharm. Sci., 90:38 (2001))and N-carboxymethyl chitosan derivatives, trimethylchitosan (see Thanouet al, Pharm. Res., 17:27 (2000)), thiolated chitosans (seeBernkop-Schnurch et al, Int. J. Pharm., 260:229 (2003)), piperazinederivatives (see PCT Publication No. WO 2007/034032 and Holappa et al,Macromol. Biosci., 6:139 (2006)), PEG-conjugated chitosan (see PCTPublication No. WO 99/01498), and those derivatives disclosed inRoberts, Chitin Chemistry, MacMillan Press Ltd., London (1992).Exemplary chitosan and chitosan derivatives which are useful additivesin the formulations of the invention include chitosan,trimethylchitosan, and chitosan-4-thio-butylamidine (see Sreenivas etal., International Journal of PharmTech Research 1:670 (2009)).

Ester Saccharides

Ester saccharides can be used in the oral dosage forms of the invention.Ester saccharides are sugar esters of a hydrophobic alkyl group (e.g.,typically from 8 to 24 carbon atoms in length). Ester saccharidesinclude ester glycosides and ester glucosides. In particularembodiments, the echinocandin class compound is formulated with a C₈₋₁₄alkyl ester of a sugar. Ester glycosides that can be used in the oraldosage forms of the invention include, without limitation, C₈₋₁₄ alkyl(e.g., octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, ortetradecyl-) esters of α or β-D-maltoside, -glucoside or -sucroside. Forexample, the echinocandin class compound can be formulated with sucrosemono-dodecanoate, sucrose mono-tridecanoate, or sucrosemono-tetradecanoate. Ester glucosides that can be used in the oraldosage forms of the invention include, without limitation, C₈₋₁₄ alkyl(e.g., octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, ortetradecyl-) esters of glucoside, such as glucose dodecanoate or glucosedecanoate.

Fatty Acids

Fatty acids can be used in the oral dosage forms of the invention. Fattyacids which can be used in the oral dosage forms of the invention, ineither their acid form, salt form, monoester form, or glyceride form,include caprylic acid (octanoic acid), pelargonic acid (nonanoic acid),capric acid (decanoic acid) and lauric acid (dodecanoic acid), and theirprimary hydroxyl forms 8-hydroxy octanoic acid, 9-hydroxy nonanoic acid,10-hydroxy decanoic acid, and 12-hydroxy dodecanoic acid.

Fatty acids are commonly derived from natural fats, oils, and waxes byhydrolysis of esters and the removal of glycerol. Fatty acids can betitrated with sodium hydroxide solution using phenophthalein as anindicator to a pale-pink endpoint. This analysis is used to determinethe free fatty acid content of fats; i.e., the proportion of thetriglycerides that have been hydrolyzed.

Short-chain fatty acids such as acetic acid (pKa=4.76 in water) aremiscible with water and dissociate to form acids. As its chain lengthincreases, fatty acids do not substantially increase in pK_(a). However,as the chain length increases the solubility of fatty acids in waterdecreases very rapidly. However, most fatty acids that are insoluble inwater will dissolve in warm ethanol.

Any alcohol can be used to produce a corresponding fatty acid ester. Thealcohols may be polyalcohols such as ethylene glycol or glycerol. Thealcohol may carry a permanent positive charge, which makes the estermucoadhesive (that is, adhesive to musoca). Methods of esterificationare well-known in the art (e.g., Fischer esterification in acid). Fattyacid esters include fatty acid ethyl esters and fatty acid methylesters.

Glycerides

Glycerides can be used in the oral dosage forms of the invention.Glycerides are fatty acid mono-, di-, and tri-esters of glycerol. Avariety of glycerides can be used as a sustained release fatty acid forthe formulation of an echinocandin class compound. Glycerides includesaturated and unsaturated monoglycerides, diglyceridies (1,2- and1,3-diglycerides), and triglycerides, with mixed and unmixed fatty acidcomposition. Each glyceride is herein designated as (Cn:m), where n isthe length of the fatty acid side chain and m is the number of doublebonds (cis- or trans-) in the fatty acid side chain. Examples ofcommercially available monoglycerides include: monocaprylin (C8; i.e.,glyceryl monocaprylate) (Larodan), monocaprin (C10; i.e., glycerylmonocaprate) (Larodan), monolaurin (C12; i.e., glyceryl monolaurate)(Larodan), monopalmitolein (C16:1) (Larodan), glyceryl monomyristate(C14) (Nikkol MGM, Nikko), glyceryl monooleate (C18:1) (PECEOL,Gattefosse), glyceryl monooleate (Myverol, Eastman), glycerolmonooleate/linoleate (OLICINE, Gattefosse), glycerol monolinoleate(Maisine, Gattefosse), and monoelaidin (C18:1) (Larodan). Examplescommercially available mono/di and tri glycerides include Capmul MCMC8EP, (C8:C10 mono/di glycerides) and Capmul MCM C10 (mono/diglycerdies). Examples commercially available diglycerides include:glyceryl laurate (Imwitor® 312, Huls), glyceryl caprylate/caprate(Capmul® MCM, ABITEC), caprylic acid diglycerides (Imwitor® 988, Huls),caprylic/capric glycerides (Imwitor® 742, Huls), dicaprylin (C8)(Larodan), dicaprin (C10) (Larodan), dilaurin (C12) (Larodan), glyceryldilaurate (C12) (Capmul® GDL, ABITEC). Examples commercially availabletriglycerides include: tricaprylin (C8; i.e., glyceryl tricaprylate)(Larodan), capatex 100 (C10), tricaprin (C10; i.e., glyceryl tricaprate)(Larodan), trilaurin (C12; i.e., glyceryl trilaurate) (Larodan),dimyristin (C14) (Larodan), dipalmitin (C16) (Larodan), distearin(Larodan), glyceryl dilaurate (C12) (Capmul® GDL, ABITEC), glyceryldioleate (Capmul® GDO, ABITEC), glycerol esters of fatty acids (GELUCIRE39/01, Gattefosse), dipalmitolein (C16:1) (Larodan), 1,2 and 1,3-diolein(C18:1) (Larodan), dielaidin (C18:1) (Larodan), and dilinolein (C18:2)(Larodan).

Hydrophilic Aromatic Alcohols

Hydrophilic aromatic alcohols can be used in the oral dosage forms ofthe invention. Hydrophilic aromatic alcohols include, withoutlimitation, phenoxyethanol, benzyl alcohol, phenylethanol, and additivedescribed in U.S. Pat. No. 7,303,762, incorporated herein by reference.

Pegylated Phospholipids

Pegylated phospholipids can be used in the oral dosage forms of theinvention. Pegylated phospholipids are additives that include apolyethylene oxide group (i.e., polyethylene glycol group) covalentlycoupled to the phospholipid, typically through a carbamate or an esterbond. Phospholipids are derived from glycerol and include a phosphateester group and two fatty acid ester groups. Suitable fatty acidsinclude saturated and unsaturated fatty acids having from eight (8) totwenty-two (22) carbons atoms (i.e., any fatty acid described herein).Representative polyethylene oxide-containing phospholipids includeC8-C22 saturated fatty acid esters of a phosphatidyl ethanolaminepolyethylene glycol salt. Representative average molecular weights forthe polyethylene oxide groups can be from about 200 to about 5000 (e.g.,PEG 200 to PEG 5000). Pegylated phospholipids include, withoutlimitation, distearoyl phosphatidyl ethanolamine polyethylene glycolsalts, such as distearoylphosphatidyl ethanolamine polyethylene glycol350 (DSPE-PEG-350) salts, distearoylphosphatidyl ethanolaminepolyethylene glycol 550 (DSPE-PEG-550) salts, distearoylphosphatidylethanolamine polyethylene glycol 750 (DSPE-PEG-750) salts,distearoylphosphatidyl ethanolamine polyethylene glycol 1000(DSPE-PEG-1000) salts, distearoylphosphatidyl ethanolamine polyethyleneglycol 1500 (DSPE-PEG-1500) salts, and distearoylphosphatidylethanolamine polyethylene glycol 2000 (DSPE-PEG-2000) salts. Mixturescan also be used. For the distearoylphosphatidyl ethanolaminepolyethylene glycol salts above, the number (e.g., 350, 550, 750, 1000,and 2000) designates the average molecular weight of the polyethyleneoxide group. Suitable distearoylphosphatidyl ethanolamine polyethyleneglycol salts include ammonium and sodium salts.

Peptide Epithelial Tight Junction Modulators

Peptide epithelial tight junction modulators can be used in the oraldosage forms of the invention. The oral dosage formulations of theinvention can include a peptide epithelial tight junction modulator. Thetight junction or zonula occludens (hereinafter “ZO”) are one of thehallmarks of absorptive and secretory epithelia (Madara, J. Clin.Invest., 83:1089-1094 (1989); and Madara, Textbook of Secretory DiarrheaEds, Lebenthal et al, Chapter 11, pages 125-138 (1990)). As a barrierbetween apical and basolateral compartments, they selectively regulatethe passive diffusion of ions and water-soluble solutes through theparacellular pathway (Gumbiner, Am. J. Physiol., 253 (Cell Physiol.22):C749-C758 (1987)). This barrier maintains any gradient generated bythe activity of pathways associated with the transcellular route(Diamond, Physiologist, 20:10-18 (1977)). Variations in transepithelialconductance can usually be attributed to changes in the permeability ofthe paracellular pathway, since the resistances of enterocyte plasmamembranes are relatively high. The ZO represents the major barrier inthis paracellular pathway, and the electrical resistance of epithelialtissues depends on the number of transmembrane protein strands, andtheir complexity in the ZO, as observed by freeze-fracture electronmicroscopy (Madara et al, J. Cell Biol., 101:2124-2133 (1985)). Sixproteins have been identified in a cytoplasmic submembranous plagueunderlying membrane contacts. ZO-1 and ZO-2 exist as a heterodimer(Gumbiner et al, Proc. Natl. Acad. Sci., USA, 88:3460-3464 (1991)) in adetergent-stable complex with ZO-3. Two other proteins, cingulin (Citiet al, Nature (London), 333:272-275 (1988)) and the 7H6 antigen (Zhonget al, J. Cell Biol., 120:477-483 (1993)) are localized further from themembrane. Rab 13, a small GTP binding protein has also recently beenlocalized to the junction region (Zahraoui et al, J. Cell Biol.,124:101-115 (1994)). Certain peptide modulators acting at ZO-1, ZO-2,ZO-3, cingulin, and/or 7H6 have been shown to be capable of reversiblyopening tight junction in the intestinal mucosa, and so, whenco-administered with a therapeutic agent, are able to effect intestinaldelivery of the therapeutic agent, when employed in an oral dosagecomposition for intestinal drug delivery (see PCT Publication No. WO96/37196; U.S. Pat. Nos. 5,665,389, 5,945,510, 6,458,925, and 6,733,762;and Fasano et al., J. Clin. Invest., 99:1158 (1997); each of which isincorporated herein by reference). An exemplary peptide epithelial tightjunction modulator is the peptide known as pn159 (see U.S. PatentPublication No. US 2006/0062758 A1, incorporated herein by reference)

Phospholipids

Phospholipids can be used in the oral dosage forms of the invention.Phospholipids are additives that include a di-fatty acid ester of aphosphorylated glycerol. Suitable fatty acids include saturated andunsaturated fatty acids having from eight (8) to twenty-two (22) carbonsatoms (i.e., any fatty acid described herein). Representativephospholipids include C8-C22 saturated fatty acid esters of phosphatidylcholine and 1-palmtoyl-2-glutaroyl-sn-glycero-3-Phosphocholine (PGPC).

Polyethylene Glycol Alkyl Ethers

Ethers of polyethylene glycol and alkyl alcohols can be used in the oraldosage forms of the invention. Preferred polyethylene glycol alkylethers include Laureth 9, Laureth 12 and Laureth 20. Other polyethyleneglycol alkyl ethers include, without limitation, PEG-2 oleyl ether,oleth-2 (Brij 92/93, Atlas/ICI); PEG-3 oleyl ether, oleth-3 (Volpo 3,Croda); PEG-5 oleyl ether, oleth-5 (Volpo 5, Croda); PEG-10 oleyl ether,oleth-10 (Volpo 10, Croda, Brij 96/97 12, Atlas/ICI); PEG-20 oleylether, oleth-20 (Volpo 20, Croda, Brij 98/99 15, Atlas/ICI); PEG-4lauryl ether, laureth-4 (Brij 30, Atlas/ICI); PEG-9 lauryl ether; PEG-23lauryl ether, laureth-23 (Brij 35, Atlas/ICI); PEG-2 cetyl ether (Brij52, ICI); PEG-10 cetyl ether (Brij 56, ICI); PEG-20 cetyl ether (Brij58, ICI); PEG-2 stearyl ether (Brij 72, ICI); PEG-10 stearyl ether (Brij76, ICI); PEG-20 stearyl ether (Brij 78, ICI); and PEG-100 stearyl ether(Brij 700, ICI).

Polyglycolized Glycerides

Polyglycolized glycerides can be used in the oral dosage forms of theinvention. Polyglycolized glycerides are mono-, di-, and tri-fatty acidesters of glycerol having at least one polyglycol (e.g., polyethyleneglycol or polypropylene glycol) moiety. Polyglycolized glycerides oftenoccur as mixtures that result from the transesterification of naturaloils with the corresponding polyglycol.

The polyglycolized glycerides useful in the formulations of theinvention can include polyethylene glycol or polypropylene glycolglyceride monoesters, diesters, and/or triesters of acetic, propionic,butyric, valeric, hexanoic, heptanoic, caprylic, nonanoic, capric,lauric, myristic, palmitic, heptadecanoic, stearic, arachidic, behenic,lignoceric, α-linolenic, stearidonic, eicosapentaenoic, docosahexaenoic,linoleic, γ-linolenic, dihomo-γ-linolenic, arachidonic, oleic, elaidic,eicosenoic, erucic, or nervonic acid, C12 fatty acids, C14 fatty acids,C16 fatty acids, and C18 fatty acids, and mixtures thereof.

Polyglycerol Fatty Acid Esters

Polyglycerol fatty acid esters can be used in the oral dosage forms ofthe invention. Polyglycerol fatty acid esters are fatty acid esters ofpolyglycerol (e.g., diglycerol, triglycerol, tetraglycerol,hexaglycerol). The polyglycerol fatty acid esters useful in theformulations of the invention can include, without limitation,polyglycerol bearing 1 to 12 fatty acid esters of valeric, hexanoic,heptanoic, caprylic, nonanoic, capric, lauric, myristic, palmitic,heptadecanoic, stearic, arachidic, behenic, lignoceric, α-linolenic,stearidonic, eicosapentaenoic, docosahexaenoic, linoleic, γ-linolenic,dihomo-γ-linolenic, arachidonic, oleic, elaidic, eicosenoic, erucic, ornervonic acid, C12 fatty acids, C14 fatty acids, C16 fatty acids, andC18 fatty acids, and mixtures thereof. Exemplary polyglycerol fatty acidesters include polyglyceryl oleate (Plurol Oleique), polyglyceryl-2dioleate (Nikkol DGDO), polyglyceryl-10 trioleate, polyglyceryl-10laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn1-0), polyglyceryl polyricinoleates (Polymuls), polyglyceryl-2 stearate(Nikkol DGMS), polyglyceryl-2 oleate (Nikkol DGMO), polyglyceryl-2isostearate Nikkol DGMIS (Nikko), polyglyceryl-3 oleate (Caprol,ABITEC), polyglyceryl-4 oleate (Nikkol Tetraglyn 1-0), polyglyceryl-4stearate (Nikkol Tetraglyn 1-S), polyglyceryl-6 oleate, polyglyceryl-10laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn1-0), polyglyceryl-10 stearate (Nikkol Decaglyn 1-S), polyglyceryl-6ricinoleate (Nikkol Hexaglyn PR-15), polyglyceryl-10 linoleate (NikkolDecaglyn 1-LN), and polyglyceryl-6 dioleate (PLUROL OLEIQUE).

Polysorbate Surfactants

Polysorbate surfactants can be used in the oral dosage forms of theinvention. Polysorbate surfactants are oily liquids derived frompegylated sorbitan esterified with fatty acids. Common brand names forPolysorbates include Alkest, Canarcel and Tween. Polysorbate surfactantsinclude, without limitation, polyoxyethylene 20 sorbitan monolaurate(TWEEN 20), polyoxyethylene (4) sorbitan monolaurate (TWEEN 21),polyoxyethylene 20 sorbitan monopalmitate (TWEEN 40), polyoxyethylene 20sorbitan monostearate (TWEEN 60); and polyoxyethylene 20 sorbitanmonooleate (TWEEN 80).

Carboxylic Acids

Carboxylic acids can be used in the oral dosage forms of the invention.Preferred carboxylic acids include citric acid, succinic acid, tartaricacid, fumaric acid, maleic acid, malonic acid, glutaric acid, adipicacid, lactic acid, malic acid, L-glutamic acid, L-aspartic acid,gluconic acid, glucuronic acid, salicylic acid, and mixtures thereof.

Polyethylene Glycols

Polyethylene glycols can be used in the oral dosage forms of theinvention. Preferred polyethylene glycols include PEG2 to PEG 5000(e.g., PEG 200, PEG 400, PEG 800, PEG 1,200, and mixtures thereof.

Taste-Masked Formulations

Taste-masked formulations can be prepared by adsorbing the additive anddrug onto a matrix (e.g., an organic matrix or inorganic matrix) to forma solid complex containing the liquid additive and drug. Exemplaryorganic matrices that can be used in the tast-masked formulations of theinvention include, without limitation, cellulose acetate, amorphouscellulose, starch, polyurethanes, polyvinyl alcohol, polyacrylates,mannitol, Avicel PH101, and Avicel PH102. Exemplary inorganic matricesthat can be used in the tast-masked formulations of the inventioninclude, without limitation, silica (e.g., Aerosil, Aeroperl, amorphoussilica, colloidal silica), silicates (e.g., Neusilin, hectrorite),carbonates (e.g., magnesium carbonate), and metal oxides (e.g.,magnesium oxide).

For example, taste-masked formulations can be prepared by adsorbing theadditive and drug onto a porous silicate (see PCT Publication No. WO00/38655). The porous silicate can be a swelling clay of the smectitetype (e.g., bentonite, veegum, laponite), hydrous aluminium silicates oralkaline earth silicates (e.g., Neusilin, hectrorite, among others), ora porous silica gel (e.g., Syloid, Porasil, Lichrosorp). In a typicaltaste-masked formulation the additive and drug are adsorbed ontosilicate selected from sodium silicate, potassium silicate, magnesiumsilicate, calcium silicate (including synthetic calcium silicate suchas, e.g., Hubersorp), zinc silicate, aluminum silicate, sodiumaluminosilicate such as, for example, Zeolex, magnesium aluminumsilicate, magnesium aluminum metasilicate, aluminum metasilicate,Neusilin UFL2 (type 1-A), Neusilin (SG2), Neusilin (F1), and Neusilin(US2), or mixtures thereof.

The taste-masked formulation can be designed to form a powder that isreconstitutable in water. The incorporation of the additive and druginto the matrix minimizes contact with the taste buds of the subject andallows the taste of the formulation to be controlled with one or moreadditional flavorings (e.g., lemon, menthol, etc.) and sweeteners (e.g.,sugars, sugar alcohols, aspartame, etc.).

Methods for making formulations for oral administration are found, forexample, in “Remington: The Science and Practice of Pharmacy” (20th ed.,ed. A. R. Gennaro, 2000, Lippincott Williams & Wilkins). Formulationsfor oral administration (e.g., tablets, pills, caplets, hard capsules,soft capsules, sachets, and liquid dosage forms) may, for example,contain any one or combination of the additives described above alongwith other additives and/or excipients as needed. Liquid-filled capsulescan include any of the additives described herein. The capsule willcontain from, for example, 10 to about 1,000 mg of an echinocandin classcompound. Liquid-filled capsules may, for example, contain eithersolutions or suspensions of an echinocandin class compound, dependingupon the concentration of echinocandin class compound within the capsuleand the additives used in the formulation.

A particular formulation of the invention can include multiple additives(e.g., a combination two or three) to achieve not only an enhancement inoral bioavailability, but also a reduced weight percentage of additivesin the formulation, allowing higher drug loadings. Thus, a combinationof (i) a fatty acid, or a salt or ester thereof, with an alkylsaccharide or ester saccharide; (ii) a glyceride with an acyl carnitine;(iii) a fatty acid, or a salt or ester thereof, with an acyl carnitine;or (iv) a glyceride with a pegylated phospholipid can be used in theoral dosage forms of the invention. These combinations of enhancers canwork synergistically to increase oral absorption of the drug over longerwindow of time, increase the overall bioavailability of the unit dosageform, and/or reduced the overall weight percentage of additive needed inthe formulation.

The echinocandin class compounds of the invention can be formulated as aclear aqueous dispersion as described in U.S. Pat. No. 6,309,663 andU.S. Patent Publication Nos. 2005/0096296, 2005/0171193, 2003/104048,2006/003493, and 2003/0215496, each of which are incorporated herein byreference. For example, a formulation of the invention can include (i)at least one hydrophilic surfactant selected from ionized ionizablesurfactants, non-ionic hydrophilic surfactants having an HLB valuegreater than or equal to about 10, and combinations thereof, and (ii) atleast one hydrophobic surfactant selected from hydrophobic (a) alcohols,polyoxyethylene alkylethers, bile acids, glycerol fatty acid monoesters,glycerol fatty acid diesters, acetylated glycerol fatty acid monoesters,acetylated glycerol fatty acid diesters, lower alcohol fatty acidmonoesters, lower alcohol fatty acid diesters, polyethylene glycol fattyacid esters, polyethylene glycol glycerol fatty acid esters,polypropylene glycol fatty acid esters, polyoxyethylene glycerides,lactic acid derivatives of mono- and diglycerides, propylene glycoldiglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fattyacid esters, polyoxyethylene-polyoxypropylene block copolymers,transesterified vegetable oils, sugar esters, sugar ethers,sucroglycerides, polyoxyethylene vegetable oils, polyoxyethylenehydrogenated vegetable oils, reaction products of polyols and at leastone member of the group consisting of fatty acids, glycerides, vegetableoils, and hydrogenated vegetable oils, and hydrophobic, (b) unionizedfatty acids, carnitine fatty acid esters, alkylsulfates, acyllactylates, mono-acetylated tartaric acid esters of mono- anddiglycerides, diacetylated tartaric acid esters of mono- anddiglycerides, succinylated monoglycerides, glyceryl stearate, citricacid esters of mono- and diglycerides, and mixtures thereof. Thehydrophilic and hydrophobic surfactants are present in amounts such thatupon mixing with an aqueous diluent at 100 times dilution, thecomposition forms a clear aqueous dispersion having an absorbance ofless than about 0.3 at 400 nm. The clear aqueous dispersion can includebile acids and/or bile salts. The composition can be included in a solidcarrier, such as a suspension in carrier in a capsule. Hyrdophilicsurfactants that can be used in this type of formulation include PEG20sorbitan monolaurate, PEG20 sorbitan monooleate, and/or polyoxyethylglycerided (e.g., PEG8 caprylic/capric glycerides).

The echinocandin class compounds of the invention can be formulated withan aryl amido C8-C10 fatty acid, or salt thereof, as described in U.S.Pat. No. 8,110,547, incorporated herein by reference. For example, aformulation of the invention can include (i)N-[8-(2-hydroxybenzoyl)amino]caprylic acid (also known as “NAC”), andsalts (SNAC) thereof, including its sodium salt; (ii)8-(N-2-hydroxy-4-methoxybenzoyl)-aminocaprylic acid (also known as“4-MOAC”), and salts thereof, including its sodium salt; (iii)N-(8-[2-hydroxybenzoyl]-amino)decanoic acid (also known as “NAD”), andsalts (SNAD) thereof, including its sodium salt; (iv)N-(8-[2-hydroxy-5-chlorobenzoyl]-amino)octanoic acid (also known as“5-CNAC”), and salts thereof, including its sodium salt; (iv)4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate (also known as “4-CNAB”),and salts thereof, including its sodium salt, or mixtures thereof.

The echinocandin class compounds of the invention can be formulatedusing a transient permeability enhancer (TPE) system as described inU.S. Pat. No. 8,241,670 and U.S. Patent Publication Nos. 2012/0009229,2010/0105627, 2011/0257095, and 2011/0311621, each of which isincorporated herein by reference. For example, a formulation of theinvention can be prepared by (i) by combining the echinocandin classcompound with a fatty acid salt (e.g., sodium octanoate, sodiumdecanoate, sodium dodecanoate, or combinations thereof) in water to forman aqueous solution; (ii) lyophilizing the aqueous solution to produce alyophilizate; and (iii) suspending the lyophilizate in a hydrophobicmedium (e.g., aliphatic molecules, cyclic molecules, di and triglycerides of long chain fatty acids, di and tri glycerides of mediumchain fatyy acids, mineral oil, paraffin, fatty acid distearate (e.g.,2-oleoyl-distearate), mono ethylene glycol distearate, cholesterolesters of fatty acids, aromatic molecules (e.g., benzyl benzolate), orcombinations thereof) to produce a suspension. The suspension canoptionally include a lecithin, a bile salt, medium chain fatty acidsalts, triglycerides, diglycerides, castor oil, and/or a non-ionicdetergent (e.g., cremophore, pegylated ethers, solid HS15, poloxamer,sorbitan fatty acid esters, glyceryl tri/mono caprylates, castor oil,triglycerides). The therapeutic composition can further include linearalcohols, branched alcohols, cyclic alcohols and combination thereof.For example, the echinocandin class compound as the sodium octanoatesalt as a lyophilizate suspended in a medium including glycerolmonocaprylate, glyceryl tricaprylate, castor oil, and/or tween 80. Thecomposition can be formulated as a dry blend, optionally in a capsule orform of a tablet.

The echinocandin class compounds of the invention can be formulated withan aromatic alcohol as described in U.S. Pat. No. 7,303,762 and U.S.Patent Publication Nos. 2006/0223746, 2006/0122097, 20004/0028736,2002/0015592, and 2012/0017602, each of which are incorporated herein byreference. Aromatic alcohols useful as absorption enhancers informulations of the invention can include hydrophilic moleculescontaining at least one aromatic ring and at least one hydroxyl group.Exemplary aromatic alcohols that can be used in the formulations of theinvention include phenoxyethanol, benzyl alcohol, phenyl ethanol, andderivatives thereof in which one or more ring protons is substituted byone or more halogen atoms, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio orC₂₋₄ alkenyl groups. Aromatic alcohols useful in the formulations of theinvention include, without limitation, butylated hydroxyl toluene,butylated hydroxyl anisole, propyl gallate, and analogues thereof. Theformulation can optionally include an amphiphile, such aspolyoxyethylene-containing surfactants with a high HLB such aspolyoxyethylene 40 monostearate, PEG200, PEG 300, PEG 400, partialglycerides (i.e., a combination of glycerol, monoglycerides, anddiglycerides), polyoxyethylene 20 cetyl ether, polysorbate 80; blockco-polymers such as Lutrol F68; bile salts such as chelate, glycholate,deoxycholate, glycodeoxycholate, chenodeoxycholate, taurodeoxycholate,ursodeoxycholate and fusidate; or amphiphilic polymers such as polyvinylpyrrolidone. The formulation can further include one or moresolubilizers capable of increasing the solubility of aromatic absorptionenhancer, such as biguanide, monoglycerides, or a linear alcohol (e.g.,ethanol). The formulation can include from 5-85%, 10-85%, 25-85%,15-70%, or 20-60% (w/w) aromatic alcohol. The formulation can beincluded in a dosage form that is enteric coated, and/or formulated as amicrodispersion in a capsule.

The echinocandin class compounds of the invention can be formulated withan omega-3 fatty acid as described in U.S. Patent Publication No.2007/0087957, incorporated herein by reference. Omega-3 fatty acidsuseful as absorption enhancers in formulations of the invention can beselected from (i) DHA (an omega-3, polyunsaturated, 22-carbon fatty acidalso referred to as 4,7,10,13,16,19-docosahexaenoic acid); (ii)alpha-linolenic acid (9,12,15-octadecatrienoic acid); (iii) stearidonicacid (6, 9, 12, 15-octadecatetraenoic acid); (iv) eicosatrienoic acid(ETA; 11,14,17-eicosatrienoic acid); (v) eicsoatetraenoic acid(8,11,14,17-eicosatetraenoic acid); (vi) eicosapentaenoic acid (EPA;5,8,11,14,17-eicosapentaenoic acid); (vii) eicosahexaenoic acid(5,7,9,11,14,17-eicosahexaenoic acid); (viii) docosapentaenoic acid(DPA; 7,10,13,16,19-docosapenatenoic acid); (ix) tetracosahexaenoic acid(6,9,12,15,18,21-tetracosahexaenoic acid); and mixtures thereof. Theformulation can include from 5-85%, 10-85%, 25-85%, 15-70%, or 20-60%(w/w) omega-3 fatty acid. The formulation can further include a bileacid, such as cholic acid, chenodeoxycholic acid, taurocholic acid,taurochenodeoxycholic acid, glycocheocholic acid, 3-β monohydroxy cholicacid, lithocholic acid, 3-α hydroxyl-12-ketocholic acid, 3-βhydroxy-12-ketocholic acid, 12-α-3-β-dihydrocholic acid,ursodesooxycholic acid, or salts thereof.

The echinocandin class compounds of the invention can be formulated withan alkyl saccharide or ester saccharide as described in U.S. Pat. No.5,661,130, or in U.S. Patent Publication Nos. 2008/0200418,2006/0046962, 2006/0045868, 2006/0024577, 2007/0298010, 2010/0209485,and 2008/0194461, each of which is incorporated herein by reference.Alkyl saccharides or ester saccharides useful as absorption enhancers informulations of the invention can be selected from dodecyl maltoside,tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate,sucrose mono-tridecanoate, sucrose mono-tetradecanoate, and mixturesthereof. The formulation can include from 0.1-1.5%, 0.5-5%, 0.75-6.5%,1.5-6.5%, or 2-10% (w/w) alkyl saccharide or ester saccharide. Theweight ratio of drug:absorption enhancer can be from 1:0.5 to 1:8.

The echinocandin class compounds of the invention can be formulated with(i) an absorption enhancer selected from acyl carnitines, acyl cholines,acyl aminoacids, phospholipids, and bile acids, or their salts; and (ii)a pH lowering agent as described in U.S. Pat. Nos. 8,093,207 and6,086,918, each of which is incorporated herein by reference. Theabsorption enhancer can be selected from lauroylcarnitine,myristoylcarnitine, palmitoylcarnitine, lauroylcholine,myristoylcholine, palmitoylcholine, hexadecyllysine,N-acylphenylalanine, N-acylglycine, and mixtures thereof. For example,the formulation can include acyl carnitine and a second absorptionenhancer selected from phospholipids, bile acids, or salts thereof. ThepH-lowering agent can be selected from citric acid, tartaric acid andamino acids. The formulation can include from 1-15%, 5-25%, 1.5-9.5%,15-25%, or 8-30% (w/w) absorption enhancer. The weight ratio of thepH-lowering agent to the absorption enhancer can be between 3:1 and20:1. Desirably, the pH-lowering agent is present in an amount such thatif a pharmaceutical composition in unit dosage form were added to tenmilliliters of 0.1M aqueous sodium bicarbonate solution, the amountwould be sufficient to lower the pH of the solution to no higher than5.5. The weigh ratio of drug:absorption enhancer can be 0.5:1 to 1:20.The formulation can further include bile acids, cationic and/or anioniccholesterol derivatives, monoglycerides, and/or linear alcohols (e.g.,ethanol).

The echinocandin class compounds of the invention can be formulated as asolid oral dosage form including (i) from about 0.5 to 70% (e.g., 0.5 to20%, 10 to 40%, 20 to 50%, or 30 to 70%) (w/w) echinocandin classcompound, or a pharmaceutically acceptable salt thereof, and (ii) fromabout 5 to 80% (e.g., 5 to 20%, 10 to 30%, 15 to 40%, or 20 to 80%)(w/w) glyceride. The glyceride can be any glyceride described herein,but preferably is selected from a mono- or di-glyceride of capric acid,a mono- or di-glyceride of caprylic acid, or a mixture of mono- anddi-glycerides of caprylic and capric acids, or a mixture of two or morethereof. The solid oral dosage form can further include a surfactantand/or oil (e.g., a non-ionic surfactant, such as ethoxylated castoroil; ethoxylated derivatives of C₅₋₂₉ mono-glycerides; polyoxyethylenederivatives of C₁₅₋₆₀ diglycerides having 1 to 90 oxyethylene (POE)repeating units; C₈₋₉₆ ethoxylated fatty esters; C₁₄₋₁₃₀ sucrose fattyesters; and polyoxyethylene derivatives of C₂₀₋₁₃₀ sorbitol and sorbitanmonoesters and triesters having 0 to 90 POE repeating units, or ananionic surfactant, such as salts of C₈₋₃₂ fatty acids; deoxycholatesalts; ursodeoxycholate salts; taurocholate salts; and sodium laurylsulfate). In the solid oral dosage forms the echinocandin classcompound, or a pharmaceutically acceptable salt thereof, is in the formof solid uniformly dispersed particles having a mean particle size offrom about 1 nm to about 1 mm. The solid dosage forms can be preparedusing the methods described in U.S. Pat. No. 7,670,626, incorporatedherein by reference. The composition can further include a biocompatibleoil.

The echinocandin class compounds of the invention can be formulated aparticle including the echinocandin class compound, wherein the particlehas an effective average diameter of less than about 2000 nm (i.e., asdetermined using light scattering methods) as described in U.S. PatentPublication No. 2009/0238867, incorporated herein by reference. Theparticulate formulation can include at least one surface stabilizerabsorbed on a surface of the particle (e.g., a surface stabilizerselected from a non-ionic surface stabilizers, ionic surfacestabilizers, cationic surface stabilizers, zwitterionic surfacestabilizers, and anionic surface stabilizers, including those identifiedin U.S. Patent Publication No. 2009/0238867, incorporated herein byreference.

Echinocandin class of compounds can be formulated with one or more ionpairing agents (e.g., cationic or anionic agents) for oral delivery. Forexample compound 22 can be modified using anionic groups of citric acidor fatty acids or bile acids to form an ionpaired composition. Theresulting complex can be formulated into biodegradable nano particles byspontaneous emulsion and solvent diffusion methods. (see Yoo et al., J.Pharmaceut. Sci. 90:194, 2001; and Quintanar-Guerrero et al.,Pharmaceut. Res. 14:119, 1997). Ion-paired formulations can be preparedfrom organic acids, such as acid salts of amino acids, or acid additionsalts (e.g., acetic, lactic, palmoic, maleic, citric, cholic acid,capric acid, caprylic acid, lauric acid, glutaric, glucuronic, glyceric,glycocolic, glyoxylic, isocitric, isovaleric, lactic, malic, oxaloacetic, oxalosuccinic, propionic, pyruvic, ascorbic, succinic, benzoic,palmitic, suberic, salicylic, tartaric, methanesulfonic,toluenesulfonic, or trifluoroacetic acid addition salts). In certainpreferred formulations, the ion-paired composition includes anabsorption enhancer, such as citric, capric, caprylic, phopsholipids andcholic acid addition salts.

Transdermal Administration

Compounds and formulations of the invention can be administeredtransdermally. To increase the rate at which the compound penetratesthrough the skin, the compound can be administered with a physicalpenetration enhancer or a chemical penetration enhancer. Physicalenhancement of skin permeation includes, for example, electrophoretictechniques, such as iontophoresis or electroporation (see U.S. Pat. Nos.6,148,232; 6,597,946; 6,611,706; 6,708,060; 6,711,435; and 6,275,728,each of which is incorporated herein by reference), includingradiofrequency cell ablation technology to enable the creation ofmicrochannels on the skin surface (see Levin et al., PharmaceuticalResearch, 22:550 (2005)). Chemical enhancers can be administered alongwith the compound to increase the permeability of the stratum corneum,and thereby provide for enhanced penetration of the compound through theskin.

Formulations for Injection

For use in the dosing regiments of the invention, echinocandin classcompounds can be formulated for intravenous infusion, bolus injection,and/or subcutaneous administration. Such formulations can optionallyinclude a bulking agent and, optionally include a surfactant excipientpackaged in a vial. The formulations are optionally reconstitutable dryformulations (e.g., freeze dried dosage forms). For example,echinocandin class compounds can be formulated for injection in saline,optionally with 0.1 to 1% (w/w) polysorbate surfactant, added as asurfactant agent. For example, the echinocandin class compounds can beformulated for injection in sterile water or aqueous buffer (e.g.,phosphate, acetate, lactate, tatarate, citrate, among others). Forexample, compound 22 can be packaged in a infusion bag containing 5%dextrose or saline solution, or prepackaged as a solid or liquidconcentration for reconstitution prior to administration.

Alternatively, the echinocandin class compounds can be incorporated intopharmaceutically-acceptable nanoparticle, nanosphere, or nanocapsuleformulations. Nanocapsules can generally entrap compounds in a stableand reproducible way. To avoid side effects due to intracellularpolymeric overloading, ultrafine particles (sized around 0.1 μm) can bedesigned using polymers able to be degraded in vivo (e.g., biodegradablepolyalkyl-cyanoacrylate nanoparticles). Such particles are described inthe prior art (see, for example, U.S. Pat. No. 5,145,684, incorporatedherein by reference). The nanoparticulate formulations typically arebetween about 5 nM and 400 nM across the largest dimension of thestructure and can be formed using a natural or artificial polymer. Thepolymers may be biodegradable, bioresorbable, or bioerodable polymersand can include, without limitation, albumin, collagen, gelatin andprolamines such as zein, polysaccharides such as alginate, cellulosederivatives and polyhydroxyalkanoates such as polyhydroxybutyratealiphatic polyesters; poly(glycolic acid) and/or copolymers thereof(e.g., poly(glycolide trimethylene carbonate); poly(caprolactoneglycolide); poly(lactic acid) and/or isomers thereof (e.g.,poly-L(lactic acid) and/or poly-D (lactic acid) and/or copolymersthereof (e.g., DL-PLA), with and without additives (e.g., calciumphosphate glass), and/or other copolymers (e.g., poly(caprolactonelactide), poly(lactide glycolide), poly(lactic acid ethylene glycol);poly(ethylene glycol) (in its various weights, i.e. 2000 D, 4000 D, 6000D, 8000 D, etc.); poly(ethylene glycol) diacrylate; poly(lactide);polyalkylene succinate; polybutylene diglycolate; polyhydroxybutyrate(PHB); polyhydroxyvalerate (PHV);polyhydroxybutyrate/polyhydroxyvalerate copolymer (PHB/PHV);poly(hydroxybutyrate-co-valerate); polyhydroxyalkaoates (PHA);polycaprolactone; poly(caprolactone-polyethylene glycol) copolymer;poly(valerolactone); polyanhydrides; poly(orthoesters) and/or blendswith polyanhydrides; poly(anhydride-co-imide); polycarbonates(aliphatic); poly(hydroxyl-esters); polydioxanone; polyanhydrides;polyanhydride esters; polycyanoacrylates; poly(alkyl 2-cyanoacrylates);poly(amino acids); poly(phosphazenes); poly(propylene fumarate);poly(propylene fumarate-co-ethylene glycol); poly(fumarate anhydrides);fibrinogen; fibrin; gelatin; cellulose and/or cellulose derivativesand/or cellulosic polymers (e.g., cellulose acetate, cellulose acetatebutyrate, cellulose butyrate, cellulose ethers, cellulose nitrate,cellulose propionate, cellophane); chitosan and/or chitosan derivatives(e.g., chitosan NOCC, chitosan NOOC-G); alginate; polysaccharides;starch; amylase; collagen; polycarboxylic acids; poly(ethylester-co-carboxylate carbonate) (and/or other tyrosine derivedpolycarbonates); poly(iminocarbonate); poly(BPA-iminocarbonate);poly(trimethylene carbonate); poly(iminocarbonate-amide) copolymersand/or other pseudo-poly(amino acids); poly(ethylene glycol);poly(ethylene oxide); poly(ethylene oxide)/poly(butylene terephthalate)copolymer; poly(epsilon-caprolactone-dimethyltrimethylene carbonate);poly(ester amide); poly(amino acids) and conventional synthetic polymersthereof; poly(alkylene oxalates); poly(alkylcarbonate); poly(adipicanhydride); nylon copolyamides; NO-carboxymethyl chitosan NOCC);carboxymethyl cellulose; copoly(ether-esters) (e.g., PEO/PLA dextrans);polyketals; biodegradable polyethers; biodegradable polyesters;polydihydropyrans; polydepsipeptides; polyarylates (L-tyrosine-derived)and/or free acid polyarylates; polyamides (e.g., Nylon 66,polycaprolactam); poly(propylene fumarate-co-ethylene glycol) (e.g.,fumarate anhydrides); hyaluronates; poly-p-dioxanone; polypeptides andproteins; polyphosphoester; polyphosphoester urethane; polysaccharides;pseudo-poly(amino acids); starch; terpolymer; (copolymers of glycolide,lactide, or dimethyltrimethylene carbonate); rayon; rayon triacetate;latex; and/pr copolymers, blends, and/or composites of above. Thenanoparticulate formulations can be used for controlled, delayed, orsustained delivery of an echinocandin class compound administered to asubject using a dosing regimen of the invention (see, for example, Chanet al., Biomaterials, 30:1627, 2009; and Gupta et al., Int. J. Res.Pharm. Sci. 1:163, 2010).

The formulations for injection can be administered, without limitation,intravenously, intramuscularly, or subcutaneously.

The formulations for injection can be stored in single unit ormulti-dose containers, for example, sealed ampules, prefilled syringes,or vials, as an aqueous solution or as a lyophilized formulation (i.e.,freeze dried) for reconstitution. The containers may any availablecontainers in the art and filled using conventional methods. Optionally,the formulation may be included in an injection pen device (or acartridge which fits into a pen device), such as those available in theart (see, e.g., U.S. Pat. No. 5,370,629), which are suitable forinjection delivery of the formulation. The formulations for injectioncan be administered using pen-injector devices, such as EasyJect®,GONAL-F® Pen, Humaject®, Novopen®, B-D® Pen, AutoPen®, Follistim®-Pen,Puregon®-Pen and OptiPen®, or Ypsomed SevoPens.

Therapy

The treatment regimens and pharmaceutical compositions described hereincan be used to treat or prevent fungal infections.

The fungal infection being treated can be an infection selected fromtinea capitis, tinea corporis, tinea pedis, onychomycosis,perionychomycosis, pityriasis versicolor, oral thrush, vaginalcandidosis, respiratory tract candidosis, biliary candidosis,eosophageal candidosis, urinary tract candidosis, systemic candidosis,mucocutaneous candidosis, aspergillosis, mucormycosis,paracoccidioidomycosis, North American blastomycosis, histoplasmosis,coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronicsinusitis. For example, the infection being treated can be an infectionby Candida albicans, C. parapsilosis, C. glabrata, C. guilliermondii, C.krusei, C. lusitaniae, C. tropicalis, Aspergillus fumigatus, A. flavus,A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus.

The treatment regimens and pharmaceutical compositions described hereincan be administered intravenously, subcutaneously, topically, orally, orby any other route described herein. In one approach, a loading-dose ofechinocandin class compound is administered to a subject in needthereof, followed by maintenance dosing administered orally.

The treatment regimens and pharmaceutical compositions described hereincan be administered to prevent a fungal infection in a subject in needthereof. For example, subjects may receive prophylaxis treatment whilebeing prepared for an invasive medical procedure (e.g., preparing forsurgery, such as receiving a transplant, stem cell therapy, a graft, aprosthesis, receiving long-term or frequent intravenous catheterization,or receiving treatment in an intensive care unit), in immunocompromisedsubjects (e.g., subjects with cancer, with HIV/AIDS, or takingimmunosuppressive agents), or in subjects undergoing long termantibiotic therapy. Alternatively, the treatment regimens andpharmaceutical compositions described herein can be administered totreat a blood stream infection or invasive infection (e.g., lung,kidney, or liver infections) in a subject.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how themethods and compounds claimed herein are performed, made, and evaluated,and are intended to be purely exemplary of the invention and are notintended to be limiting.

Example 1. Pharmacokinetics Following Intravenous Administration inBeagle Dogs

Echinocandin class compounds were administered to beagle dogs weighingapproximately 6-10 kg. Each compound was dosed at 1.4 mg/kg in aqueoussaline (with or without 0.5% Tween) over course of 1-10 minutes.Diphenhydramine was kept on hand in case the dogs demonstrated ahistamine response. The dogs were fasted at least 12 hours prior to eachdosing and offered food after the 4-hour blood sample was taken; waterwas withheld for 1 hour prior to and 4 hours following each dosingevent. The dose for each animal was based on its most recent bodyweight. The test article was injected intravenously via a catheterplaced in the cephalic vein as a slow bolus.

Blood was collected via the jugular vein. All blood samples (1 mL each)were collected into K₃EDTA tubes. Following blood collection, thesamples were immediately inverted several times and were held on wet icepending centrifugation. The samples were centrifuged within 30 minutesof collection under refrigeration (˜5° C. for 10 minutes at ˜2000 g) toobtain plasma. The plasma was frozen immediately on dry ice afterseparation. The plasma samples were stored at approximately −70° C.until analysis.

Plasma (100 μL) was precipitated with 400 μL of 0.1% formic acid inacetonitrile containing the internal standard (100 ng/mL pneumocandin).The samples were then capped and vortexed for about 30 seconds followedby centrifugation at 14,000 rpm at room temperature for 10 minutes.Following centrifugation 200 μL of supernatant was transferred toplastic autosampler vials containing 200 μL of 0.1% formic acid in waterand vortexed. Samples were then analyzed by LCMSMS.

All pharmacokinetic calculations were performed using WinNonlin version4.1 (Pharsight Corp) by noncompartmental analysis. The results areprovided in Table 1, below.

TABLE 1 PK Values following intravenous dosing in dogs. Volume ofDistri- Mean AUC Cmax T_(1/2) bution clearance Compound (hr · ng/mL)(ng/mL) (Hr) (mL/kg) (mL/min/kg) Anidulafungin 27833 3230 11.6 779 0.785Compound 22 48700 1570 53.1 1360 0.301 Compound 26 67167 4080 33.7 6270.219 Compound 37 46200 2660 27.6 874 0.365 Compound 19 96100 7700 18.9331 0.202 Compound 21 113000 6740 28.9 361 0.145 Compound 39 50800 363021.0 687 0.377

Example 2. Formulation for Oral Administration

The following formulations can be used in the methods, kits, andcompositions of the invention.

Exemplary oral formulations of the invention are described in Table 2.

TABLE 2 Formulation Composition Concentration Formulation 1 Echinocandinclass 10.0 mg/mL compound Dodecyl Maltoside 3% (w/w) Tween 20 1% (w/w)Saline 96% (w/w) Formulation 2 Echinocandin class 10.0 mg/mL (emulsion)compound Labrasol ® 40% (w/w) Plurol Oleique 10% (w/w) Labrafac ® 6.25%(w/w) Propylene glycol 6.25% (w/w) Water 37.5% (w/w) Formulation 3Echinocandin class 10.0 mg/mL compound Mono glyceryl decanoate 4% (w/w)Tricparin 4% (w/w) Tween 20 1.5% (w/w) Tween 80 0-0.8% (w/w) NaOAcbuffer (0.1M, pH 5-6) 90.5% (w/w) Formulation 4 Echinocandin class 10.0mg/mL compound Laureth 12 6.07% (w/w) Tween 20 1.16% (w/w) Saline 92.8%(w/w) Formulation 5 Echinocandin class 10.0 mg/mL compound Sodiumcaprate 3% (w/w) Sodium laurate 3% (w/w) Phosphate buffer (0.1M, 94%(w/w) pH 7.4) Formulation 6 Echinocandin class 7.5 mg/mL compoundChitosan (low MW) 3% (w/w) NaOAc buffer (0.1M, pH 5-6) 90.5% (w/w)Formulation 7 Echinocandin class 10.0 mg/mL compound DL Palmitoylcarnitine 5% (w/w) NaOAc buffer (0.1M, pH 5-6) 95% (w/w) Formulation 8Echinocandin class 10.0 mg/mL compound DPPS 5% (w/w) NaOAc buffer (0.1M,pH 5-6) 95% (w/w) Formulation 9 Echinocandin class 2.2% (w/w) compoundPropylene glycol 19.3% (w/w) Peceol 67.6% (w/w) DSPE-PEG2000 13% (w/w)Formulation 10 Echinocandin class 2.2% (w/w) compound Capmul MCM C8, EP25.5% (w/w) Glycerol 55.7% (w/w) Propylene glycol 15.3% (w/w)Formulation 11 Echinocandin class 10.0 mg/mL (saline) compound Tween 200-0.5% (w/w) Saline 99.5% (w/w) Formulation 12 Echinocandin class 11.4mg/mL compound Sodium caprate 6% (w/w) Phosphate buffer (0.1M, 94% (w/w)pH 7.8) Formulation 13 Echinocandin class 1.9% (w/w) (liquid filled gel)compound Propylene glycol 18.8% (w/w) Peceol 75.1% (w/w) DSPE-PEG20004.2% (w/w) Formulation 14 Echinocandin class 15% (w/w) (gelfilled dryblend) compound DL Palmitoyl carnitine 75% (w/w) Sodium citrate 10%(w/w) Formulation 15 Echinocandin class 4.3% (w/w) (liquid filled gel)compound Capric acid 32.8% (w/w) Propylene glycol 18.1% (w/w) Trolamine31.8% (w/w) PEG200 11.4% (w/w) Formulation 16 Echinocandin class 17.7%(w/w) (immediate release compound tablet) Sodium caprate 29.9% (w/w)Sodium laurate 29.4% (w/w) Mannitol 17.7% (w/w) Explotab 4.8% (w/w) NaStearyl Fumarate 0.4% (w/w) Formulation 17 Echinocandin class 17.2%(w/w) (immediate release compound tablet) DL Palmitoyl carnitine 60.1%(w/w) Mannitol 17.3% (w/w) Explotab 5.1% (w/w) Na Stearyl Fumarate 0.3%(w/w) Formulation 18 Echinocandin class 1.5% (w/w) compound Sesame oil71.5% (w/w) Glyceryl monostearate 1.5% (w/w) Tween 20 0.8% (w/w) NaOAc,0.1M, pH 5-6 24.8% (w/w) Formulation 19 Echinocandin class 1.0% (w/w)compound Citric acid 5.0% (w/w) Sterile water 96.0% (w/w) Formulation 20Echinocandin class 1.0% (w/w) compound PEG400 99.0% (w/w)

Example 3. Pharmacokinetics Following Oral Administration in Beagle Dogs

Echinocandin class compounds were administered to beagle dogs weighingapproximately 6-10 kg. Each animal received the appropriate preparedtest article in a single oral capsule dose at a target dose level ofabout 7-10 mg/kg. Immediately after dosing, each animal was offered 20mL-30 mL of water orally (Groups 1-4) or 30 mL of water orally to assistin swallowing the capsule.

Animals were treated and blood samples were drawn and analyzed asprovided in Example 1.

The bioavailability of each oral dose formulation was estimated bycomparison to intravenous plasma concentration data in dogs fromExample 1. The results provided in Table 3 show the oral bioavailabilityfor the echinocandin class compound in saline (formulation 11), and theimprovement over saline with the use of a formulation of the invention.

TABLE 3 Oral Dosing Results¹ % BA in Improvement³ Compound saline²Formulation (% BA) Anidulafungin 7.80% 5 2.1 (16.5%) 1 1.8 (14.3%) 3 1.3(9.80%) 4 NI⁴ 2 NI 6 NI Compound 22 3.50% 5 3.5 (12.3%) 1 2.3 (8.21%) 32.8 (9.76%) 7 3.5 (12.2%) 8 NI 9 NI 10 NI 16 1.5 (5.50%) 17 3.3 (11.8%)12 NI 13 2.5 (8.80%) 14 4.3 (15.0%) 15 3.8 (13.4%) Compound 26 NA⁵ 6 NI5 NI 7 NI Compound 37 NA⁵ 5 NI 1 NI 3 NI 7 NI Compound 19 5.74% 5 NI 1NI Compound 21 4.70% 5 NI 1 1.3 (6.42%) 7 NI Compound 39 5.15% 5 NI 1 NI¹All percent oral bioavailabilities are calculated from AUC data.²Percent oral bioavailability in formulation 11. ³Improvement reportedas the ratio of the percent oral bioavailability for a formulationdivided by the oral bioavailability when formulated in saline. ⁴NI = noimprovement in oral bioavailability in comparison to saline. ⁵NA = notavailable. Improvement evaluated based on observed oral bioavailabilityfor other compounds of Table 3 in saline.

Improvements in oral bioavailability were observed for formulationsincluding fatty acids or salts thereof (formulations 5, 14, 15, and 16),glycerides (formulations 3 and 13), acyl carnitines (formulations 7, 14,and 17), alkyl saccharides (formulation 1), and pegylated phospholipids(formulation 13).

The largest improvements in oral bioavailability were observed foranidulafungin and compound 22.

Example 4. Dissolution Profile of Tableted Formulation 17

A dissolution study of the tablet of formulation 17 was performed using500 mL of 100 mM Acetate Buffer pH 5.2 as the medium. The methodutilized Apparatus 2 with a paddle speed of 50 rpm, a tablet sinker, andthe run time was 60 minutes. After the dissolution was complete, thesamples were analyzed for compound 22 content using HPLC. The HPLCmethod was a gradient method using an Agilent Zorbax Bonus-RP column(250×4.6 mm) (column temperature of 60° C., wavelength of 300 nm, withMobile Phase A=33 mM sodium pentanesulfonate pH 4.0 and Mobile PhaseB=acetonitrile). The samples were injected neat with an injection volumeof 15 μL.

The results of the dissolution study are provided in Table 4.

TABLE 4 Sample Time % Compound 22 (Minutes) Dissolved 5 23 10 48 15 6230 93 45 96 60 97

The tablet of formulation 17 has an immediate release profile (i.e.,over 80% dissolved within 30 minutes). Thus, formulation 17 allows forthe simultaneous release of permeation enhancing additive and compound22. The substantially simultaneous release of both the active andexcipients is necessary to achieve an increase in oral bioavailability.

Example 5. Aqueous Formulation of Compound 22 for Injection

The solubility of compound 22 was measured in aqueous buffers of varyingpH to assess this compound's suitability for formulation in an aqueouscarrier for administration by injection (e.g., intravenous bolus,intravenous infusion, subcutaneous, or intramuscular injection).

The results are provided in Table 5 (below) along with anidulafungin asa comparison. Compound 22 was found to have dramatically greater aqueoussolubility than anidulafungin in a variety of aqueous mediums.

TABLE 5 Solubility (mg/mL)¹ Aqueous Medium Anidulafungin Compound 22Sterile Water for injection <0.01 >142 90% Water:10% glycerol<0.01 >102.3 Acetate buffer (0.01M, pH 4.5) <0.01 >145 Acetate buffer(0.01M, pH 5.5) <0.01 >141 Tris buffer (0.01M, pH 8.5) <0.01 >138¹Solubility in mg/mL of salt free equivalent of compound 22. Allmeasurements made at ambient temperature for acetate salt. Point ofsaturation was not achieved in these measurements for compound 22.

Example 6. Intravenous Infusion of Compound 22

Compound 22 can be supplied in a single-use vial of sterile lyophilizedmaterial. Compound 22 can be reconstituted in sterile water andsubsequently diluted with 5% dextrose injection or 0.9% sodium chlorideinjection, USP (normal saline) for infusion into a subject.

A vial containing a quantity of compound 22 can be reconstituted with avolume of sterile water, or another suitable aqueous carrier, to providea concentration of about 3.3 mg/mL.

Content of the reconstituted vial(s) can be transferred into anappropriately sized IV infusion bag containing either 5% dextroseinjection, USP or 0.45% to 0.9% sodium chloride.

Exemplary doses and volumes are provided in Table 6 (below)

TABLE 6 Total Infusion solution Dose Reconstituted Infusion infusionconcentration (mg) volume (mL) volume (mL) volume (mL) (mg/mL) 50 15 5065 0.77 100 30 100 130 0.77 200 60 200 260 0.77

Example 7. Stability of Compound 22 and Anidulafungin in VariousMammalian Plasmas and in PBS

Stock solutions of compound 22 and anidulafungin were prepared in DMSOat a concentration of 1 mg/mL. Plasma samples were prepared by mixingplasma with 10% volume of 1 M sodium phosphate, pH 7.4, to minimize pHfluctuation, and stock solution to produce plasma samples containingapproximately 10,000 ng/mL compound 22 or anidulafungin. For thestability experiments in PBS buffer, plasma was replaced with phosphatebuffered saline, pH 7.4. The DMSO concentration was 1% in the finalincubation. Multiple individual aliquots (0.5 mL each) were prepared,capped, and incubated at 37° C. At each stability time point, thereaction was stopped by removing the sample from the incubator andadding 0.5 mL of acetonitrile containing internal standard. Samples werecentrifuged for approximately 5 minutes at 10000 rpm to precipitate theproteins. Stability was measured in five different matrices (i.e. ratplasma, dog plasma, monkey plasma, human plasma, and PBS). An aliquot(100 μL) of supernatant of each sample was assayed by HPLC. Thepercentage of anidulafungin and compound 22 remaining at each time pointwas calculated by dividing the peak area ratio at each time point by thepeak area ratio at time zero.

TABLE 7 Anidulafungin (% remaining) Time Dog Human Monkey Rat (h) plasmaplasma plasma PBS plasma 0  100%  100%  100%  100%  100% 1  100%  102% 106%  100% 84.3% 2 94.8% 98.0%  111% 97.8% 76.5% 4 77.1% 61.8% 68.1%87.4% 45.6% 8 81.1% 72.0% 76.0% 86.0% 23.2% 21 47.2% 51.2% 22.4% 68.9% 7.3% 44 14.6%  7.3% 13.8% 41.9%  7.4%

TABLE 8 Compound 22 (% remaining) Time Dog Human Monkey Rat (h) plasmaplasma plasma PBS plasma 0  100%  100% 100% 100% 100% 1 97.9% 98.5% 109%105% 103% 2  107%  101% 110% 103% 106% 4  119%  125% 143% 107% 138% 894.0% 97.5% 115% 101% 99.3%  21 87.3% 95.7% 104% 96.3%  96.5%  44 78.6%93.3% 93.5%  96.1%  91.2% 

In all test systems (plasma from rat, dog, monkey, human and PBS),compound 22 showed greater stability than anidulafungin. Considering aprimary mechanism of clearance for anidulafungin in vivo is chemicaldegradation, and considering that compound 22 displays slowerdegradation both in plasma and in buffer, this greater stability ofcompound 22 in various matrices is likely a contributing factor in theslower clearance observed for this compound. Thus, the increasedstability may ultimately enable a less frequent dosing regimen than whatis required of echinocandins with less stability.

The stability in plasma observed for compound 22 is necessary, but notsufficient, to permit its use in a dosing regimen in which atherapeutically effective steady state concentration is achieved withless frequent dosing.

Example 8. Pharmacokinetics of Compound 22 and Anidulafungin inChimpanzee

Pharmacokinetic studies were performed in six adult female chimpanzees.Two chimpanzees received 1-mg/kg IV dose of compound 22 formulated in 5%dextrose (60-minute infusion). Two chimpanzees received 10-mg/kg oraldose of compound 22 formulated in 5% citric acid (oral bolus). Twochimpanzees received 1-mg/kg IV dose of anidulafungin formulated aspackage label (5% dextrose, 60-minute infusion). Plasma samples werecollected from all chimps for 10 days to 22 days. PK curves are depictedin FIGS. 16A, 16B, and 18. All pharmacokinetic calculations wereperformed using WinNonlin version 4.1 (Pharsight Corp) bynoncompartmental analysis. The results are provided in Table 9 and 10,below.

TABLE 9 Compound 22 IV and Oral PK in Chimpanzees PK parameters (mean of2 chimps) Clearance 3.4 mL/h/kg Volume of 0.4 L/kg distribution Plasmahalf-life 81 h (IV) 99 h (PO) Oral bioavailability 4.5%

TABLE 10 Anidulafungin IV PK Data in Chimpanzees PK parameters (mean of2 chimps) Clearance 25 mL/h/kg Volume of distribution 1.1 L/kg Plasmahalf-life (IV) 30 h Oral bioavailability —

Compound 22 exhibits a longer half-life and lower clearance (higher AUCfor given dose) than does anidulafungin in chimpanzees. Based on PK datafor caspofungin (literature) and anidulafungin (Seachaid), it appearsthat the chimp is a good model for echinocandin PK (see FIGS. 17A-17C,human (solid lines) and chimp (dotted lines) from 1-mg/kg IV dose).Existing studies on this class of compounds in humans and chimpanzeessuggest that the human clearance will be equal or lower (i.e. “better”)than values observed from the chimpanzee.

The PK performance of compound 22 administered orally to chimpanzees wasalso evaluated. Compound 22 formulated with 5% citric acid resulted inan oral bioavailability of 4-5%. Levels of 600 to 1200 ng/mL wereachieved after a single oral dose in chimps (see FIG. 18). The lowclearance and long half-life of compound 22 should enable QD/BID oraldosing that permits accumulation or maintanence of therapeutic plasmaconcentrations. For example, compound 22 can be administered every 5-8days as an intravenous infusion or bolus. Alternatively, compound 22 canbe administered in an intravenous loading dose, followed by maintenancedosing for as long as is desired to maintain a therapeutically effectivecirculating concentration. Furthermore, the desirable pharmacokineticproperties of compound 22 allow for less frequent dosing.

Example 9. Half Lives of Echinocandins in Mammals

The circulating half lives of echinocandin class compounds are providedin Table 11.

TABLE 11 Half-life (h) Compound Organism Caspofungin MicafunginAnidulafungin 22* Mouse 6-7  7-13 14-20 44-71 Rat 6-7 5 18, 22* 30 DogNA NA 12*, 15  53 Monkey 5-6 (rhesus) NA  8* 40 Chimpanzee 6-7 — 30* 81Rabbit 2-3 3 4-6 — Man  9-11 10-17 24-26 — *measurements from assaysconducted by applicant, others are literature values.

Example 10. Formulation for Subcutaneous and/or Intravenous BolusAdministration of Compound 22

The following formulations can be used in the methods, kits, andcompositions of the invention. Exemplary subcutaneous and/or intravenousbolus formulations of the invention are described in Table 12.

TABLE 12 Formulation Composition Concentration Formulation SC1 Compound22 2.42% (w/w) Tween 20 1.44% (w/w) 100 mM Acetate Buffer pH 96.14%(w/w) 4.5 Formulation SC2 Compound 22 0.28% (w/w) Tween 20 0.40% (w/w)10 mM Acetate Buffer pH 99.32% (w/w) 4.5 Formulation SC3 Compound 221.38% (w/w) Tween 20 0.39% (w/w) 50 mM Acetate Buffer pH 98.23% (w/w)4.5 Formulation SC4 Compound 22 16.5% (w/w) Tween 20 0.8% (w/w) 10 mMAcetate Buffer pH 82.7% (w/w) 5.5 Formulation SC5 Compound 22 21.5%(w/w) Sterile water (pH adjusted 78.5% (w/w) to 5.5) Formulation SC6Compound 22 17.3% (w/w) Sterile water (pH adjusted 67.7% (w/w) to 6.0)Glycerol, USP 15.0% (w/w) Formulation SC7 Compound 22 13.0% (w/w) Tween20 4.4% (w/w) 10 mM Acetate Buffer pH 86.6% (w/w) 6.0

Example 11. Formulation for Intravenous Infusion of Compound 22

The following formulations can be used in the methods, kits, andcompositions of the invention. Exemplary intravenous infusionformulations of the invention are described in Table 13. Theformulations can be added to an IV bag for infusion into a subject.

TABLE 13 Formulation Composition Concentration Formulation IV1 Compound22 0.33% (w/w) Sterile water 99.67% (w/w) Formulation IV2 Compound 220.33% (w/w) 20 mM Sodium Acetate, pH 99.67% (w/w) 4.5 Formulation IV3Compound 22 0.33% (w/w) 20 mM Sodium Acetate, pH 99.67% (w/w) 6.0Formulation IV4 Compound 22 0.33% (w/w) 20 mM Sodium Lactate, pH 99.67%(w/w) 4.5 Formulation IV5 Compound 22 0.33% (w/w) 20 mM Sodium Lactate,pH 99.67% (w/w) 6.0 Formulation IV6 Compound 22 0.33% (w/w) Tween 801.0% (w/w) 30 mM Sodium Lactate, pH 98.67% (w/w) 4.5 Formulation IV7Compound 22 0.33% (w/w) Tween 80 1.0% (w/w) 30 mM Sodium Lactate, pH98.67% (w/w) 6.0 Formulation IV8 Compound 22 0.33% (w/w) Tween 80 0.60%(w/w) Mannitol 0.66% (w/w) 30 mM Sodium Lactate, pH 98.41% (w/w) 4.5Formulation IV9 Compound 22 0.33% (w/w) Tween 80 0.60% (w/w) Mannitol0.66% (w/w) 30 mM Sodium Lactate, pH 98.41% (w/w) 6.0 Formulation IV10Compound 22 0.33% (w/w) Fructose 0.33% (w/w) Mannitol 0.66% (w/w) 20 mMSodium Lactate, pH 98.68% (w/w) 4.5 Formulation IV11 Compound 22 0.33%(w/w) Fructose 0.33% (w/w) Mannitol 0.66% (w/w) 20 mM Sodium Lactate, pH98.68% (w/w) 6.0 Formulation IV12 Compound 22 0.33% (w/w) Mannitol 0.66%(w/w) 20 mM Sodium Lactate, pH 99.0% (w/w) 6.0 Formulation IV13 Compound22 0.33% (w/w) Mannitol 0.66% (w/w) 20 mM Sodium Lactate, pH 99.0% (w/w)5.0 Formulation IV14 Compound 22 0.33% (w/w) Tween 80 0.60% (w/w)Mannitol 1.32% (w/w) 30 mM Sodium Lactate, pH 97.75% (w/w) 6.0

Example 12. Lyophilized Formulations for Intravenous Infusion ofCompound 22

The following lyophilized formulations can be used in the methods, kits,and compositions of the invention. Exemplary lyophilized formulations ofthe invention are described in Table 14. The formulations can bereconstituted and added to an IV bag for infusion into a subject.

TABLE 14 Formulation Composition Concentration Formulation L1 Compound22 66.79% (w/w) Sodium Acetate buffer, pH 33.21% (w/w) 4.5 FormulationL2 Compound 22 66.79% (w/w) Sodium Acetate buffer, pH 33.21% (w/w) 6.0Formulation L3 Compound 22 25% (w/w) Mannitol 50% (w/w) Fructose 25%(w/w) Formulation L4 Compound 22 24.9% (w/w) Mannitol 49.8% (w/w) SodiumLactate buffer 25.2% (w/w) Formulation L5 Compound 22 24.81% (w/w) Tween80 75.19% (w/w) Formulation L6 Compound 22 21.27% (w/w) Tween 80 64.44%(w/w) Sodium Lactate buffer, pH 14.30% (w/w) 6.0 Formulation L7 Compound22 21.40% (w/w) Mannitol 42.81% (w/w) Fructose 21.40% (w/w) SodiumLactate buffer, pH 14.39% (w/w) 4.5 Formulation L8 Compound 22 17.16%(w/w) Mannitol 34.31% (w/w) Tween 80 31.23% (w/w) Sodium Lactate buffer,pH 17.30% (w/w) 6.0 Formulation L9 Compound 22 17.16% (w/w) Mannitol34.31% (w/w) Tween 80 31.23% (w/w) Sodium Lactate buffer, pH 17.30%(w/w) 4.5 Formulation L10 Compound 22 14.65% (w/w) Mannitol 29.30% (w/w)Fructose 14.65% (w/w) Tween 80 26.67% (w/w) Sodium Lactate buffer, pH14.73% (w/w) 4.5

Example 13. Pharmacokinetics of Compound 22 Subcutaneously (SC)Administered

Pharmacokinetic studies were performed in rats (2.8 mg/kg IV, 2.8 mg/kgSC injection to the back, 2.8 mg/kg SC injection to the abdomen, and 2.8mg/kg SC injection to the hind foot) and Chinese cynomolgus monkeys(2.13 mg/kg IV and 2.8 mg/kg SC). Blood samples were collected from eachanimal at predetermined times after dosing. Whole blood samples werecentrifuged to isolate plasma. The plasma samples were analyzed forcompound 22 using LC-MS/MS.

The SC monkey study was performed using formulation SC1 (see Table 12).The rat studies were performed using formulation SC2 (see Table 12) forthe abdomen and back injections, and formulation SC3 (see Table 12) forthe hind foot injection. The PK curves are depicted in FIG. 19 (rat) and20 (monkey). The results demonstrate that the regimens of the inventioncan include one or more subcutaneous administrations to produce atherapeutically effective circulating concentration of compound 22.

Example 14. Stability

Compound 22 exhibits commercially acceptable stability upon storage as asolid or in solution.

Solutions of compound 22 formulated for injection in 5% DextroseSolution (at 1.3 mg/mL and 1.1 mg/mL) and in 0.9% Sterile SalineSolution (1.3 mg/mL) were stored at room temperature in a clear vialunder ambient light and monitored for decomposition by HPLC. Allsolutions exhibited only minor losses in potency (less than 5%) over aperiod of 4 months.

Accelerated aging at 40° C. in a clear vial under ambient light wasperformed for compound 22 formulated with 5% Dextrose Solution (3.3mg/mL), 20 mM Acetate Buffer pH 4.5 (3.3 mg/mL), and 20 mM Lactate pH6.0 (3.3 mg/mL). All solutions exhibited only minor losses in potency(less than 5%) over a period of 4 months.

Lyophilized formulations L6 and L7 (see Table 14) were observed toexhibit only minor losses in potency (less than 5%) over a period of 3months.

No stabilizers were utilized in the stability studies.

Other Embodiments

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are within the claims.

1-71. (canceled)
 72. A method of treating a subject having orsusceptible to a fungal infection comprising administering to thesubject an aqueous solution comprising compound 22 having the formula

or a pharmaceutically acceptable salt thereof, wherein the aqueoussolution is administered to the subject intravenously, in an amount thatis sufficient to treat the fungal infection.
 73. The method of claim 72,wherein the aqueous solution is administered at an interval of one doseevery 5 to 8 days.
 74. The method of claim 73, wherein the interval isone dose every 7 days.
 75. The method of claim 72, wherein the aqueoussolution is intravenously administered for at least two intervals over aperiod of at least two weeks.
 76. The method of claim 75, wherein theaqueous solution is intravenously administered for at least four weeks.77. The method of claim 75, wherein the aqueous solution isintravenously administered for at least eight weeks.
 78. The method ofclaim 75, wherein the aqueous solution is intravenously administered forat least twelve weeks.
 79. The method of claim 72, wherein thepharmaceutically acceptable salt of compound 22 is an acetate salt. 80.The method of claim 72, wherein the subject is being prepared for aninvasive medical procedure, is immunocompromised, or is undergoinglong-term antibiotic therapy.
 81. The method of claim 80, wherein theinvasive medical procedure is a transplant, a stem cell therapy, agraft, a prosthesis, an intravenous catheterization, or treatment in anintensive care unit.